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Cited by 544Neuroscience and Neuropharmacology ResearchSchizophrenia research and treatmentAutism Spectrum Disorder Research

Common Mechanisms of Excitatory and Inhibitory Imbalance in Schizophrenia and Autism Spectrum Disorders

Open access
Gao, R., Penzes, P.·2015·Current Molecular Medicine
DOI 10.2174/1566524015666150303003028PMC PMC4721588
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Abstract

Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations. Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism. Thus, understanding the molecular underpinnings of E/I imbalance may provide essential insight into the etiology of these disorders and may uncover novel targets for future drug discovery. Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.

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Written from the paper’s full text.

TL;DR

This review argues that autism spectrum disorder (ASD) and schizophrenia (SCZ), despite distinct genetic architectures, converge on disrupted excitatory/inhibitory (E/I) balance in cortical circuits. It synthesizes genetic, postmortem, physiological, and animal-model evidence for shared glutamatergic and GABAergic mechanisms, including mTOR and NMDA receptor pathways.

Key findings

  • E/I ratios are developmentally and cell-type specific: cultured hippocampal pyramidal dendrites shift from 2:1 at 14 days to 4:1 at 19 days, while hippocampal parvalbumin and calretinin interneurons show 14:1 and 3:1 ratios, respectively.
  • In SCZ, postmortem work links gray matter loss and reduced spine density in dorsolateral prefrontal cortex, auditory cortex, and hippocampus to working memory, hallucination, and memory deficits; PV+ interneurons show lower parvalbumin and GAD67 mRNA without loss of cell number, and gamma oscillations (30–80 Hz) are abnormal.
  • In ASD, early brain overgrowth occurs in about 25–30% of children between years 1 and 2, epilepsy in about 30%, and postmortem tissue shows increased spine density in some cortical layers but also contradictory simplified dendrites; GABAergic markers (GAD65/GAD67, GABA receptors, PV+ interneurons) are altered.
  • Shared risk genes and pathways include NRG1/ErbB4, DISC1, 22q11 deletion, neurexins/neuroligins, SHANK, MeCP2, FMRP, CNTNAP2, mTOR, and NMDAR hypofunction; 22q11 deletion accounts for up to 1–2% of SCZ cases, and Rett syndrome has epilepsy in 80% of cases.

Methods

  • Narrative review with no primary experiments; synthesizes genetic linkage/GWAS, postmortem neuropathology, electrophysiology, imaging, and mouse/animal model studies.
  • Organizes evidence by disorder and circuit: SCZ and ASD separately across glutamatergic and GABAergic systems, then convergent mTOR and NMDAR signaling pathways.
  • No systematic search, inclusion criteria, or meta-analysis described.

Limitations

  • Authors caution that ASD postmortem evidence is limited by small samples (about 120 brains since 1980) and lack of closely matched controls; syndromic autism models (TSC, PTEN, FXS, Rett) are genetically and pathologically distinct from idiopathic autism, so their mechanisms may not fully generalize.
  • Authors note unresolved discrepancies, such as ErbB4 pre- versus postsynaptic localization and NL4 synaptic localization.
  • Evident from the text: conclusions rely heavily on animal models and narrative synthesis; many genetic associations are weak and heterogeneous, with individual genes explaining little risk.

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Integrity signals

Registry

Crossref · 10.2174/1566524015666150303003028

Cites

341 of 341 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 340 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    Alterations to excitatory/inhibitory circuits are key to the pathogenesis of ASD and SCZ.

    “Here, we review key genetic, physiological, neuropathological, functional, and pathway studies that suggest alterations to excitatory/inhibitory circuits are keys to ASD and SCZ pathogenesis.”
    Quote in the paperSubstantial claim
  • Premisereasoning

    Several lines of evidence support E/I imbalance as a shared pathophysiological mechanism in ASD and SCZ.

    “Multiple lines of evidence implicate imbalances in excitatory and inhibitory activity (E/I imbalance) as a shared pathophysiological mechanism.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Because ASD and SCZ are heterogeneous, many studies lack the power to consistently reproduce weak associations.

    “Moreover, given the conditions’ heterogeneous natures, many studies lack the required power to consistently reproduce these weak associations [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Owen MJ Williams NM O’Donovan MC The molecular genetics of schizophrenia: new findings promise new insights Mol Psychiatry 2004 9 1 14 27 14581932

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  • Premisecitation

    Gray matter loss is one of the defining neuropathological features of SCZ.

    “One of the defining neuropathological features of SCZ is gray matter loss [51–53].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [51] Selemon LD Goldman-Rakic PS The reduced neuropil hypothesis: a circuit based model of schizophrenia Biological psychiatry 1999 45 1 17 25 9894571

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    • cites [52] Thompson PM Vidal C Giedd JN Mapping adolescent brain change reveals dynamic wave of accelerated gray matter loss in very early-onset schizophrenia Proceedings of the National Academy of Sciences of the United States of America 2001 98 20 11650 5 11573002 PMC58784

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    • cites [53] Vita A De Peri L Deste G Sacchetti E Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies Transl Psychiatry 2012 2 e190 23168990 PMC3565772

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  • Premisecitation

    Some autism patients have auditory and visual hallucinations, similar to acutely ill SCZ patients.

    “In addition, subsets of autism patients have auditory and visual hallucinations, similarly to acutely ill patients with SCZ [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Toal F Bloemen OJ Deeley Q Psychosis and autism: magnetic resonance imaging study of brain anatomy Br J Psychiatry 2009 194 5 418 25 19407271

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  • May combine two claims. 117
  • Classified as probably not a substantial claim. 11
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation

    Social interaction deficits, cognitive deficits, emotional processing problems, and executive function dysfunction are behavioral features commonly observed in both ASD and SCZ.

    “The behavioral symptoms of ASD and SCZ, however, are intriguingly similar; social interaction deficits, cognitive deficits, emotional processing problems, and executive functions dysfunction are all behavioral features commonly observed in both disorders [6, 7].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Rapin I Tuchman RF Autism: definition, neurobiology, screening, diagnosis Pediatr Clin North Am 2008 55 5 1129 46 viii 18929056

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    • cites [7] Cheung C Yu K Fung G Autistic disorders and schizophrenia: related or remote? An anatomical likelihood estimation PLoS One 2010 5 8 e12233 20805880 PMC2923607

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  • May combine two claims.

    Premisecitation

    ASD and SCZ are highly heritable spectrum disorders with complicated genetic etiologies and overlapping behavioral phenotypes.

    “Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are two highly heritable spectrum disorders with complicated genetic etiologies but overlapping behavioral phenotypes [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] de Lacy N King BH Revisiting the relationship between autism and schizophrenia: toward an integrated neurobiology Annu Rev Clin Psychol 2013 9 555 87 23537488

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ASD and SCZ are cognitive disorders with complex genetic architectures and overlapping behavioral phenotypes, which points to shared pathway disturbances.

    “Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are cognitive disorders with complex genetic architectures but overlapping behavioral phenotypes, which suggests common pathway perturbations.”
    • Also stated in: § INTRODUCTION · plain
      “Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are two highly heritable spectrum disorders with complicated genetic etiologies but overlapping behavioral phenotypes [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] de Lacy N King BH Revisiting the relationship between autism and schizophrenia: toward an integrated neurobiology Annu Rev Clin Psychol 2013 9 555 87 23537488

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genetic linkage and GWAS have found many disease-associated genes, but few are widely reproducible because each gene likely has small influence on overall disease pathogenesis.

    “Genetic linkage and genome-wide association studies (GWAS) have discovered a plethora of disease-associated genes, but few have been widely reproducible because each individual gene likely holds small influence on the overall disease pathogenesis [3, 4]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Harrison PJ Weinberger DR Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence Mol Psychiatry 2005 10 1 40 68 image 5 15263907

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    • cites [4] Toro R Konyukh M Delorme R Key role for gene dosage and synaptic homeostasis in autism spectrum disorders Trends Genet 2010 26 8 363 72 20609491

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  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    Alterations in the ratio of excitatory to inhibitory cortical activity could explain the similar social and cognitive deficits in ASD and SCZ.

    “One emerging hypothesis maintains that alterations in the ratio of excitatory to inhibitory cortical activity (E/I imbalance) could explain the diseases’ similar social and cognitive deficits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Gamma oscillations arise from synchronized firing of interconnected excitatory glutamatergic and primarily inhibitory fast-spiking GABAergic PV+ interneurons, and their power is modulated by E/I balance at distinct synaptic sites and intrinsic excitable properties.

    “Gamma oscillations emerge from the synchronized firing of interconnected excitatory glutamatergic and primarily inhibitory fast-spiking GABAergic PV+ interneurons (Fig. 2), and its power (i.e. amplitude) is modulated by the E/I balance at distinct synaptic sites in the circuit and the intrinsic excitable properties of the neurons [46].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [46] Bartos M Vida I Jonas P Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks Nat Rev Neurosci 2007 8 1 45 56 17180162

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    Premisecitation

    NRG1 and ERBB4 are two of the most reproducible SCZ candidate genes.

    “NRG1 and ERBB4 are two of the most reproducible SCZ candidate genes [69–76].”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [69] Stefansson H Sigurdsson E Steinthorsdottir V Neuregulin 1 and susceptibility to schizophrenia Am J Hum Genet 2002 71 4 877 92 12145742 PMC378543

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    • cites [70] Hall J Whalley HC Job DE A neuregulin 1 variant associated with abnormal cortical function and psychotic symptoms Nat Neurosci 2006 9 12 1477 8 17072305

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    • cites [71] Munafo MR Thiselton DL Clark TG Flint J Association of the NRG1 gene and schizophrenia: a meta-analysis Mol Psychiatry 2006 11 6 539 46 16520822

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    • cites [72] Munafo MR Attwood AS Flint J Neuregulin 1 genotype and schizophrenia Schizophr Bull 2008 34 1 9 12 18032396 PMC2632377

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    • cites [73] Silberberg G Darvasi A Pinkas-Kramarski R Navon R The involvement of ErbB4 with schizophrenia: association and expression studies Am J Med Genet B Neuropsychiatr Genet 2006 141B 2 142 8 16402353

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    • cites [74] Law AJ Kleinman JE Weinberger DR Weickert CS Disease-associated intronic variants in the ErbB4 gene are related to altered ErbB4 splice-variant expression in the brain in schizophrenia Hum Mol Genet 2007 16 2 129 41 17164265

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    • cites [75] Nicodemus KK Law AJ Radulescu E Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls Arch Gen Psychiatry 2010 67 10 991 1001 20921115 PMC4291187

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    • cites [76] Tan W Dean M Law AJ Molecular cloning and characterization of the human ErbB4 gene: identification of novel splice isoforms in the developing and adult brain PLoS One 2010 5 9 e12924 20886074 PMC2944867

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    Premisecitation

    Chronic activity blockade with TTX and bicuculline increased and decreased miniature excitatory postsynaptic current amplitude, respectively, in cultured neurons, and drug washout restored firing rates to control levels.

    “Turrigiano et al. [39] discovered chronic activity blockade with tetrodotoxin (TTX) and bicuculline increased and decreased the amplitude of miniature excitatory postsynaptic currents (mEPSC) respectively in cultured neurons, while drug washout restored firing rates to control levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Turrigiano GG Leslie KR Desai NS Rutherford LC Nelson SB Activity-dependent scaling of quantal amplitude in neocortical neurons Nature 1998 391 6670 892 6 9495341

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    Premisecitation

    DISC1 was originally identified through a disruption in its open reading frame in a large Scottish pedigree and later verified as a legitimate SCZ risk gene through polymorphisms and frame shift mutations in other SCZ-afflicted lineages.

    “DISC1 was originally identified through a disruption in its open reading frame in a large Scottish pedigree [90] and later verified to be a legitimate SCZ risk gene through polymorphisms and frame shift mutations in other SCZ-afflicted lineages [91].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [90] Millar JK Wilson-Annan JC Anderson S Disruption of two novel genes by a translocation co-segregating with schizophrenia Hum Mol Genet 2000 9 9 1415 23 10814723

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    • cites [91] Schumacher J Laje G Abou Jamra R The DISC locus and schizophrenia: evidence from an association study in a central European sample and from a meta-analysis across different European populations Hum Mol Genet 2009 18 14 2719 27 19414483 PMC2701338

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Glutamatergic synapses are found almost exclusively on dendritic spines, whereas GABAergic synapses are localized along the dendritic shaft, somata, and axon initial segments.

    “While glutamatergic synapses are found almost exclusively on dendritic spines [2], GABAergic synapses are localized along the dendritic shaft, somata, and axon initial segments [15].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] Penzes P Cahill ME Jones KA VanLeeuwen JE Woolfrey KM Dendritic spine pathology in neuropsychiatric disorders Nat Neurosci 2011 14 3 285 93 21346746 PMC3530413

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    • cites [15] Fritschy JM Brunig I Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications Pharmacol Ther 2003 98 3 299 323 12782242

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    Premisecitation

    Long-term NRG1 treatment increases pyramidal neuronal spine density and the proportion of spines with mature phenotypes.

    “Long-term NRG1 treatment increases pyramidal neuronal spine density and the preponderance of spines with mature phenotypes [84]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Barros CS Calabrese B Chamero P Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system Proceedings of the National Academy of Sciences of the United States of America 2009 106 11 4507 12 19240213 PMC2657442

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  • May combine two claims.

    Premisecitation

    ErbB4 is found at much higher levels in interneuron excitatory synapses, especially in the PV+ subtype, and an in vivo study demonstrated ErbB4 specificity in controlling cortical GABAergic circuit development.

    “Perplexingly, ErbB4 is found at much higher levels in interneuron excitatory synapses - especially belonging to the PV+ interneuron subtype - and a recent study used in vivo techniques to directly demonstrate ErbB4’s specificity in controlling cortical GABAergic circuit development [87].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [87] Fazzari P Paternain AV Valiente M Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling Nature 2010 464 7293 1376 80 20393464

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  • May combine two claims.

    Interpretationnone given

    PV+ interneurons are essential for proper cognitive function and are noticeably affected in ASD and SCZ patients.

    “For the purposes of this review, we will focus largely on PV+ interneurons because they play an essential role in proper cognitive function and are noticeably afflicted in ASD and SCZ patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Circuits are malleable but vulnerable during postnatal development, and several neurodevelopmental disorders such as ASD and SCZ manifest during this plasticity period.

    “Thus, circuits tend to be malleable but vulnerable during postnatal development; notably, several neurodevelopmental disorders, such as ASD and SCZ, manifest during this plasticity period [49, 50].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Zoghbi HY Postnatal neurodevelopmental disorders: meeting at the synapse? Science 2003 302 5646 826 30 14593168

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    • cites [50] Fatemi SH Folsom TD The neurodevelopmental hypothesis of schizophrenia, revisited Schizophr Bull 2009 35 3 528 48 19223657 PMC2669580

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  • May combine two claims.

    Premisecitation

    ErbB4 overexpression increases spine density, area, and excitatory synaptic transmission, while ErbB4 knockdown reduces spine density and size.

    “Similarly, ErbB4 over-expression increases spine density, area, and excitatory synaptic transmission while ErbB4 knockdown reduces spine density and size [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Li B Woo RS Mei L Malinow R The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity Neuron 2007 54 4 583 97 17521571 PMC2031848

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  • May combine two claims.

    Interpretationcitation

    E/I imbalances may arise from problems in initial neural circuit formation or maintenance, because many genes from linkage and association studies code for proteins involved in these processes.

    “Such imbalances may arise from problems in initial neural circuit formation or maintenance, as many of the genes derived from linkage and association studies code for proteins involved with these processes [4, 11].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Toro R Konyukh M Delorme R Key role for gene dosage and synaptic homeostasis in autism spectrum disorders Trends Genet 2010 26 8 363 72 20609491

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    • cites [11] Penzes P Buonanno A Passafaro M Sala C Sweet RA Developmental vulnerability of synapses and circuits associated with neuropsychiatric disorders J Neurochem 2013 126 2 165 82 23574039 PMC3700683

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  • May combine two claims.

    Premisecitation

    Multiple postmortem studies have reproducibly found lower parvalbumin mRNA and GAD67 levels in DLPFC PV+ neurons in SCZ, while the absolute number of PV+ cells is unchanged, suggesting a functional rather than numerical deficit.

    “Interestingly, multiple postmortem studies have reproducibly found lower levels of parvalbumin mRNA and GAD67, the principal synthesizing enzyme for GABA, in DLPFC PV+ neurons, but found the absolute number of PV+ cells unchanged, suggesting a functional rather than a numerical deficit [64, 65].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [64] Lewis DA Hashimoto T Volk DW Cortical inhibitory neurons and schizophrenia Nat Rev Neurosci 2005 6 4 312 24 15803162

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    • cites [65] Hashimoto T Volk DW Eggan SM Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia J Neurosci 2003 23 15 6315 26 12867516 PMC6740534

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  • May combine two claims.

    Premisecitation

    Mice lacking ErbB4 in the CNS show reduced spine density in hippocampus and cortex and exhibit schizophrenia-related behavioral phenotypes.

    “In addition, mice lacking ErbB4 in the CNS show reduced spine density in both the hippocampus and cortex and exhibit schizophrenia-related behavioral phenotypes [84].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Barros CS Calabrese B Chamero P Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system Proceedings of the National Academy of Sciences of the United States of America 2009 106 11 4507 12 19240213 PMC2657442

      Not checked in the free run.

    • Rests on an assumption: Behavioral phenotypes in rodent models described as schizophrenia-like or autism-like correspond to the human disorders.

  • May combine two claims.

    Premisecitation

    Loss of TSC1 in hippocampal cultures caused a primary decrease in inhibitory synaptic transmission, followed by a futile secondary homeostatic response, and ended with increased network hyperexcitability.

    “Bateup et al. [47] showed loss of TSC1, a gene encoding a regulator of mTOR signaling (see mTOR and ASD) in hippocampal cultures resulted in a primary decrease of inhibitory synaptic transmission, followed closely by a futile secondary homeostatic response, and concluded with an overall increase in network hyperexcitability.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Bateup HS Johnson CA Denefrio CL Saulnier JL Kornacker K Sabatini BL Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis Neuron 2013 78 3 510 22 23664616 PMC3690324

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    Premisecitation

    A SCZ-associated SNP in the transmembrane domain of NRG1 disrupts gamma-secretase-dependent cleavage, reduces NRG1-mediated intracellular signaling, and abolishes NRG1-regulated growth of pyramidal dendrites.

    “For instance, a SCZ-associated SNP in the transmembrane domain of NRG1 leads to disruptions in gamma-secretase dependent cleavage of the protein, which in turn reduces NRG1-mediated intracellular signaling and abolishes NRG1-regulated growth of pyramidal dendrites [88].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Chen Y Hancock ML Role LW Talmage DA Intramembranous valine linked to schizophrenia is required for neuregulin 1 regulation of the morphological development of cortical neurons J Neurosci 2010 30 27 9199 208 20610754 PMC2919805

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    Premisecitation

    DTNBP1-knockout mice have reduced excitability of cortical and striatal PV+ interneurons, which in turn leads to hyperexcitable pyramidal cells.

    “DTNBP1-knockout mice have reductions in the excitability of cortical and striatal PV+ interneurons, which in turn lead to hyperexcitable pyramidal cells [134].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [134] Ji Y Yang F Papaleo F Role of dysbindin in dopamine receptor trafficking and cortical GABA function Proceedings of the National Academy of Sciences of the United States of America 2009 106 46 19593 8 19887632 PMC2780743

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    Premisecitation

    Mice with full or PV+ targeted ablation of ErbB4 exhibit reductions in kainate-induced gamma oscillation power and severe SCZ-like behaviors.

    “Similarly, mice harboring full or PV+ targeted ablation of ErbB4 exhibit reductions in kainate induced gamma oscillation power and exhibit severe SCZ-like behaviors [123–125].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [123] Fisahn A Neddens J Yan L Buonanno A Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia Cereb Cortex 2009 19 3 612 8 18632742 PMC2638818

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    • cites [124] Wen L Lu YS Zhu XH Neuregulin 1 regulates pyramidal neuron activity via ErbB4 in parvalbumin-positive interneurons Proceedings of the National Academy of Sciences of the United States of America 2010 107 3 1211 6 20080551 PMC2824309

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    • cites [125] Shamir A Kwon OB Karavanova I The importance of the NRG-1/ErbB4 pathway for synaptic plasticity and behaviors associated with psychiatric disorders J Neurosci 2012 32 9 2988 97 22378872 PMC3302154

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    • Rests on an assumption: Behavioral phenotypes in rodent models described as schizophrenia-like or autism-like correspond to the human disorders.

  • May combine two claims.

    Premisecitation

    DISC1 is a scaffold protein involved in hippocampal development and found abundantly at spines, where it facilitates formation of protein complexes.

    “DISC1 is a scaffold protein intimately involved with hippocampal development [98–100] and is found abundantly at the spines [101], where it facilitates the formation of protein complexes with its coiled-coil rich C-terminal domain.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [98] Austin CP Ky B Ma L Morris JA Shughrue PJ Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development Neuroscience 2004 124 1 3 10 14960334

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    • cites [99] Enomoto A Asai N Namba T Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus Neuron 2009 63 6 774 87 19778507

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    • cites [100] Meyer KD Morris JA Disc1 regulates granule cell migration in the developing hippocampus Hum Mol Genet 2009 18 17 3286 97 19502360 PMC2722990

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    • cites [101] Kirkpatrick B Xu L Cascella N Ozeki Y Sawa A Roberts RC DISC1 immunoreactivity at the light and ultrastructural level in the human neocortex J Comp Neurol 2006 497 3 436 50 16736468

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  • May combine two claims.

    Premisecitation

    ErbB4 cell-autonomously regulates formation of excitatory synapses on PV+ chandelier and basket cells and formation of inhibitory synapses from PV+ subtypes onto neighboring pyramidal cells.

    “2) ErbB4 cell-autonomously regulates the formation of excitatory synapses on these inhibitory subtypes and the formation of inhibitory synapses from PV+ subtypes onto neighboring pyramidal cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Fazzari P Paternain AV Valiente M Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling Nature 2010 464 7293 1376 80 20393464

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    Premisecitation

    Perfusion of hippocampal slices with small doses of NRG1 increased kainate-induced gamma oscillations; this effect was ErbB4-dependent, blocked by an ErbB4 antagonist, and absent in ERBB4-knockout mice.

    “Recently, it was demonstrated that perfusion of hippocampal slices with small doses of NRG1 led to increases in kainate-induced gamma oscillations. This effect was ErbB4-dependent, as it was blocked with an ErbB4 antagonist and was absent in ERBB4-knockout mice [123].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [123] Fisahn A Neddens J Yan L Buonanno A Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia Cereb Cortex 2009 19 3 612 8 18632742 PMC2638818

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    Premisecitation

    ErbB4 is expressed in nearly all PV+ interneurons in the neocortex and in over half in the hippocampus.

    “More specifically, ErbB4 is expressed in nearly all PV+ interneurons in the neocortex [120] and over half in the hippocampus [123].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] Neddens J Buonanno A Expression of the neuregulin receptor ErbB4 in the brain of the rhesus monkey (Macaca mulatta) PLoS One 2011 6 11 e27337 22087295 PMC3210802

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    • cites [123] Fisahn A Neddens J Yan L Buonanno A Neuregulin-1 modulates hippocampal gamma oscillations: implications for schizophrenia Cereb Cortex 2009 19 3 612 8 18632742 PMC2638818

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    Premisecitation

    Synchronization of cortical and hippocampal neural networks at gamma frequencies is important for proper cognition, memory, and learning, but is perturbed in schizophrenic patients.

    “Synchronization of cortical and hippocampal neural networks at gamma frequencies (30–80) Hz is important for proper cognition, memory, and learning [108], but are perturbed in schizophrenic patients [58, 109, 110].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [108] Engel AK Singer W Temporal binding and the neural correlates of sensory awareness Trends Cogn Sci 2001 5 1 16 25 11164732

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    • cites [58] Gonzalez-Burgos G Lewis DA GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia Schizophr Bull 2008 34 5 944 61 18586694 PMC2518635

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    • cites [109] Herrmann CS Demiralp T Human EEG gamma oscillations in neuropsychiatric disorders Clin Neurophysiol 2005 116 12 2719 33 16253555

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    • cites [110] Spencer KM The functional consequences of cortical circuit abnormalities on gamma oscillations in schizophrenia: insights from computational modeling Front Hum Neurosci 2009 3 33 19876408 PMC2769552

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    Premisecitation

    In SCZ patients carrying high-risk DISC1 SNPs, DISC1-interacting protein expression levels, but not DISC1 mRNA levels, are drastically reduced, suggesting DISC1 function might be affected.

    “In SCZ patients carrying high risk DISC1 SNPs, DISC1-interacting protein expression levels, but not DISC1 mRNA levels, are drastically reduced [102], suggesting that DISC1 function might be affected in SCZ.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Lipska BK Peters T Hyde TM Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs Hum Mol Genet 2006 15 8 1245 58 16510495

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    Premisecitation

    Early brain overgrowth and neuronal hyperexcitability are two well-established phenotypes in ASD.

    “Early brain overgrowth and neuronal hyperexcitability are two well-established phenotypes in ASD [135, 136].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [135] Parellada M Penzol MJ Pina L The neurobiology of autism spectrum disorders Eur Psychiatry 2014 29 1 11 9 24275633

      Not checked in the free run.

    • cites [136] Rubenstein JL Merzenich MM Model of autism: increased ratio of excitation/inhibition in key neural systems Genes, brain, and behavior 2003 2 5 255 67 PMC6748642 14606691

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  • May combine two claims.

    Premisecitation

    The Rac-GEF Kalirin-7 has been identified as a DISC1 interacting partner and directly regulates DISC1's effects on spine morphology through Rac1.

    “Recently, the Rac-GEF Kalirin-7 has been identified as a DISC1 interacting partner and has been shown to directly regulate DISC1’s effects on spine morphology through Rac1 [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Hayashi-Takagi A Takaki M Graziane N Disrupted-in-Schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1 Nat Neurosci 2010 13 3 327 32 20139976 PMC2846623

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  • May combine two claims.

    Premisecitation

    A KALRN-knockout mouse shows severe reductions in spine density in the frontal cortex and schizophrenic-like behaviors during adolescent years.

    “Finally, a KALRN-knockout mouse shows severe reductions in spine density in the frontal cortex and schizophrenic-like behaviors during adolescent years [105].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Cahill ME Xie Z Day M Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes Proceedings of the National Academy of Sciences of the United States of America 2009 106 31 13058 63 19625617 PMC2722269

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    • Rests on an assumption: Behavioral phenotypes in rodent models described as schizophrenia-like or autism-like correspond to the human disorders.

  • May combine two claims.

    Premisecitation

    The 22q11 microdeletion syndrome is the most common copy number variant associated with SCZ and accounts for up to 1-2% of cases.

    “The 22q11 microdeletion syndrome is the most common copy number variant (CNV) associated with SCZ and accounts for up to 1–2% of the cases [106].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [106] Stark KL Xu B Bagchi A Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model Nat Genet 2008 40 6 751 60 18469815

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  • May combine two claims.

    Premisecitation

    The fragile X brain is characterized by macrocephaly, elevated spine density, and elongated, tortuous spine morphologies.

    “For instance, the fragile X brain is characterized by macrocephaly, elevated spine density and elongated, tortuous spine morphologies [139].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Irwin SA Patel B Idupulapati M Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination Am J Med Genet 2001 98 2 161 7 11223852

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  • May combine two claims.

    Premisecitation

    In vivo experiments demonstrated that ErbB4 is expressed in axon terminals and post-synaptic excitatory synapses of PV+ chandelier and basket cells, but not in pyramidal cells.

    “1) ErbB4 is expressed both in the axon terminals and post-synaptic excitatory synapses of PV+ chandelier and basket cells, but not in pyramidal cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Fazzari P Paternain AV Valiente M Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling Nature 2010 464 7293 1376 80 20393464

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Thirty percent of autistic individuals struggle with epilepsy.

    “while 30% struggle with epilepsy [138].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Tuchman R Rapin I Epilepsy in autism Lancet Neurol 2002 1 6 352 8 12849396

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  • May combine two claims.

    Premisecitation

    Mutant mice overexpressing a dominant negative form of DISC1 have reduced PV+ immunoreactivity in the prefrontal cortex, suggesting DISC1 is necessary for proper functioning of GABAergic cortical interneurons.

    “For instance, mutant mice that overexpress a dominant negative form of DISC1 have reduced PV+ immunoreactivity in the prefrontal cortex, suggesting DISC1 is necessary for proper functioning of GABAergic cortical interneurons [129].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Hikida T Jaaro-Peled H Seshadri S Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans Proceedings of the National Academy of Sciences of the United States of America 2007 104 36 14501 6 17675407 PMC1964873

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  • May combine two claims.

    Premisecitation

    Knockout mice lacking all three α-Nrxns or NLs 1-3 show little change in total synapse number but exhibit severe synaptic transmission phenotypes, implicating Nrxn-NLs in synaptic function but not formation in vivo.

    “Knockout mice lacking all three α-Nrxns or NLs 1–3 show little change in total number of synapses but exhibit severe synaptic transmission phenotypes [159, 160], thereby implicating Nrxn-NLs in synaptic function, but not formation, in vivo.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [159] Missler M Zhang W Rohlmann A Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis Nature 2003 423 6943 939 48 12827191

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    • cites [160] Varoqueaux F Aramuni G Rawson RL Neuroligins determine synapse maturation and function Neuron 2006 51 6 741 54 16982420

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  • May combine two claims.

    Premisecitation

    NLGN3-knockout mice have reduced ultrasound vocalization, deficits in social novelty preference, and reduced brain volume.

    “NLGN3-knockout mice have reduced ultrasound vocalization, deficits in social novelty preference, and brain volume reduction”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [194] Radyushkin K Hammerschmidt K Boretius S Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit Genes, brain, and behavior 2009 8 4 416 25 19243448

      Not checked in the free run.

    • cites [195] Jamain S Radyushkin K Hammerschmidt K Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism Proceedings of the National Academy of Sciences of the United States of America 2008 105 5 1710 5 18227507 PMC2234209

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  • May combine two claims.

    Interpretationreasoning

    Neurexins and neuroligins may contribute to ASD pathogenesis through control of synaptic function, and their deregulation may cause neurodevelopmental imbalances in synaptic transmission that progress to behavioral changes.

    “In summary, neurexins and neuroligins may contribute to ASD pathogenesis through its control of synaptic function; deregulation may result in neurodevelopmental imbalances of synaptic transmission and may progress to behavioral changes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Neuroligins (NL1-4) are postsynaptic cell adhesion proteins that interact with presynaptic Neurexins (Nrxns 1-3) to form trans-synaptic adhesions.

    “Neuroligins (NL1-4) are a group of postsynaptic cell adhesion proteins [154] which interact with presynaptic Neurexins (Nrxns 1–3) to form trans-synaptic adhesions [155–158].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [154] Sudhof TC Neuroligins and neurexins link synaptic function to cognitive disease Nature 2008 455 7215 903 11 18923512 PMC2673233

      Not checked in the free run.

    • cites [155] Ichtchenko K Hata Y Nguyen T Neuroligin 1: a splice site-specific ligand for beta-neurexins Cell 1995 81 3 435 43 7736595

      Not checked in the free run.

    • cites [156] Ichtchenko K Nguyen T Sudhof TC Structures, alternative splicing, and neurexin binding of multiple neuroligins J Biol Chem 1996 271 5 2676 82 8576240

      Not checked in the free run.

    • cites [157] Comoletti D Flynn RE Boucard AA Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins Biochemistry 2006 45 42 12816 27 17042500

      Not checked in the free run.

    • cites [158] Chih B Gollan L Scheiffele P Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex Neuron 2006 51 2 171 8 16846852

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kwon et al. showed that synapse formation in vivo specifically depended on transcellular differences in NL1 levels between neighboring neurons, suggesting nascent neurons compete for limited presynaptic neurexin ligands, with cells expressing more NL1 forming synapses more readily.

    “Kwon et al. [163] showed that synapse formation in vivo was specifically dependent on transcellular differences in NL1 levels between neighboring neurons, suggesting that nascent neurons compete for limited presynaptic neurexin ligands, with cells expressing more NL1 forming synapses more readily.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [163] Kwon HB Kozorovitskiy Y Oh WJ Neuroligin-1-dependent competition regulates cortical synaptogenesis and synapse number Nat Neurosci 2012 15 12 1667 74 23143522 PMC3536444

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  • May combine two claims.

    Premisecitation

    Point mutants in NLGN3, NLGN4, or NRXN1, truncations of NLGN4 or NRXN1, chromosomal rearrangements of regions harboring NRXN1, NLGN1, or NLGN2, and a promoter mutation in NLGN4 have been identified in ASD.

    “Both groups have been genetically linked with ASD: point mutants in NLGN3, NLGN4, or NRXN1 [165–169] truncations of NLGN4 or NRXN1 [170–172], chromosomal rearrangements of regions harboring NRXN1, NLGN1, or NLGN2 [173, 174], and a promoter mutation in NLGN4 [175] have been identified.”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [165] Comoletti D De Jaco A Jennings LL The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing J Neurosci 2004 24 20 4889 93 15152050 PMC6729460

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    • cites [166] Etherton MR Tabuchi K Sharma M Ko J Sudhof TC An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus EMBO J 2011 30 14 2908 19 21642956 PMC3160244

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    • cites [167] Zhang C Milunsky JM Newton S A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export J Neurosci 2009 29 35 10843 54 19726642 PMC2777970

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    • cites [168] Feng J Schroer R Yan J High frequency of neurexin 1beta signal peptide structural variants in patients with autism Neurosci Lett 2006 409 1 10 3 17034946

      Not checked in the free run.

    • cites [169] Jamain S Quach H Betancur C Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism Nat Genet 2003 34 1 27 9 12669065 PMC1925054

      Not checked in the free run.

    • cites [170] Lawson-Yuen A Saldivar JS Sommer S Picker J Familial deletion within NLGN4 associated with autism and Tourette syndrome Eur J Hum Genet 2008 16 5 614 8 18231125

      Not checked in the free run.

    • cites [171] Zahir FR Baross A Delaney AD A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha J Med Genet 2008 45 4 239 43 18057082

      Not checked in the free run.

    • cites [172] Gauthier J Siddiqui TJ Huashan P Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia Hum Genet 2011 130 4 563 73 21424692 PMC3204930

      Not checked in the free run.

    • cites [173] Konstantareas MM Homatidis S Chromosomal abnormalities in a series of children with autistic disorder J Autism Dev Disord 1999 29 4 275 85 10478727

      Not checked in the free run.

    • cites [174] Kim HG Kishikawa S Higgins AW Disruption of neurexin 1 associated with autism spectrum disorder Am J Hum Genet 2008 82 1 199 207 18179900 PMC2253961

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  • May combine two claims.

    Premisecitation

    All three Shank family members are linked to ASD susceptibility, with de novo mutations in SHANK3, SHANK2, and SHANK1 identified in individuals with ASD.

    “All three members of the Shank family of have been linked with ASD susceptibility: a large number of de novo mutations in SHANK3 [197–199], in SHANK2 [200], and in SHANK1 [201] have been identified in individuals with ASD.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [197] Durand CM Betancur C Boeckers TM Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders Nat Genet 2007 39 1 25 7 17173049 PMC2082049

      Not checked in the free run.

    • cites [198] Moessner R Marshall CR Sutcliffe JS Contribution of SHANK3 mutations to autism spectrum disorder Am J Hum Genet 2007 81 6 1289 97 17999366 PMC2276348

      Not checked in the free run.

    • cites [199] Gauthier J Spiegelman D Piton A Novel de novo SHANK3 mutation in autistic patients Am J Med Genet B Neuropsychiatr Genet 2009 150B 3 421 4 18615476

      Not checked in the free run.

    • cites [200] Berkel S Marshall CR Weiss B Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation Nat Genet 2010 42 6 489 91 20473310

      Not checked in the free run.

    • cites [201] Sato D Lionel AC Leblond CS SHANK1 Deletions in Males with Autism Spectrum Disorder Am J Hum Genet 2012 90 5 879 87 22503632 PMC3376495

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Heterogeneous changes in glutamatergic and GABAergic systems in the ASD brain can converge on an overall increased ratio of excitation to inhibition, which can manifest as epileptic symptoms, macroscopic brain volume changes, and behavioral alterations.

    “Together, these results suggest heterogenous changes in glutamatergic and GABAergic systems in the ASD brain can converge upon an overall increased ratio of excitation/inhibition, which can manifest in epileptic symptoms, macroscopic changes in brain volume, and behavioral alterations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    α-NRXN1-knockout mice show hippocampal E/I imbalance caused by reduced spontaneous excitatory post-synaptic currents and reduced prepulse inhibition.

    “α-NRXN1-knockout mice have hippocampal E/I imbalance due to decreased spontaneous excitatory post-synaptic currents and decreased prepulse inhibitions”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [181] Etherton MR Blaiss CA Powell CM Sudhof TC Mouse neurexin-1alpha deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments Proceedings of the National Academy of Sciences of the United States of America 2009 106 42 17998 8003 19822762 PMC2764944

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  • May combine two claims.

    Premisecitation

    SHANK1-knockout mice have small dendritic spines, weakened synaptic transmission, and defects in social communication.

    “SHANK1-knockout mice have small dendritic spines, weakened synaptic transmission [203], and defects in social communication [204].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [203] Hung AY Futai K Sala C Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1 J Neurosci 2008 28 7 1697 708 18272690 PMC2633411

      Not checked in the free run.

    • cites [204] Wohr M Roullet FI Hung AY Sheng M Crawley JN Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior PLoS One 2011 6 6 e20631 21695253 PMC3111434

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    SHANK genes cause alterations in excitatory synaptic morphology and signaling and in behavioral characteristics, making them useful animal models for studying synaptic pathology in ASD.

    “Overall, these studies demonstrate that the SHANK genes cause alterations in excitatory synaptic morphology and signaling, as well as changes in behavior characteristics, suggesting they are good animal models for the study of synaptic pathology in ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Rett syndrome presents at 6-18 months with autistic-like deficiencies in speech, social and motor skills, especially repetitive movements, and results from functional loss of one copy of MECP2.

    “Rett Syndrome is a neurodevelopmental disorder that presents at around 6–18 months with autistic-like deficiencies in speech, social and motor skills - particularly repetitive movements - which results from the functional loss of one copy of the MECP2 gene [227, 228].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [227] Chahrour M Zoghbi HY The story of Rett syndrome: from clinic to neurobiology Neuron 2007 56 3 422 37 17988628

      Not checked in the free run.

    • cites [228] Guy J Cheval H Selfridge J Bird A The role of MeCP2 in the brain Annu Rev Cell Dev Biol 2011 27 631 52 21721946

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  • May combine two claims.

    Premisecitation

    TSC1, TSC2, and PTEN each regulate synaptic structure.

    “each of these proteins regulates synaptic structure [213–215].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [213] Kwon CH Luikart BW Powell CM Pten regulates neuronal arborization and social interaction in mice Neuron 2006 50 3 377 88 16675393 PMC3902853

      Not checked in the free run.

    • cites [214] Tavazoie SF Alvarez VA Ridenour DA Kwiatkowski DJ Sabatini BL Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2 Nat Neurosci 2005 8 12 1727 34 16286931

      Not checked in the free run.

    • cites [215] Fraser MM Bayazitov IT Zakharenko SS Baker SJ Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities Neuroscience 2008 151 2 476 88 18082964 PMC2278004

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  • May combine two claims.

    Premisecitation

    SHANK2-knockout mice show behavioral abnormalities, impaired social activities, hyperactivity, and synaptic transmission defects.

    “the SHANK2-knockout mice, like their SHANK3-knockout counterparts, show abnormalities in behavior tests, impairment in social activities, hyperactivity, and defects in synaptic transmission [208, 209].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [208] Schmeisser MJ Ey E Wegener S Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2 Nature 2012 486 7402 256 60 22699619

      Not checked in the free run.

    • cites [209] Won H Lee HR Gee HY Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function Nature 2012 486 7402 261 5 22699620

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  • May combine two claims.

    Premisecitation

    NL3 is predominantly localized to excitatory synapses and is also found to a lesser extent in GABAergic synapses.

    “while NL3 is predominantly localized to excitatory synapses [184], it is also found to a lesser extent in GABAergic synapses [183].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [184] Graf ER Zhang X Jin SX Linhoff MW Craig AM Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins Cell 2004 119 7 1013 26 15620359 PMC2826211

      Not checked in the free run.

    • cites [183] Budreck EC Scheiffele P Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses Eur J Neurosci 2007 26 7 1738 48 17897391

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  • May combine two claims.

    Premisecitation

    Behavioral defects in SHANK3 mutant mice correlate with impaired basal synaptic transmission at CA3-CA1 connections, reduced GluR1 clusters and protein levels in hippocampus, and major changes in striatal and corticostriatal synapses.

    “The behavioral defects of SHANK3 mutant mice correlate with impaired basal synaptic transmission in CA3-CA1 connections, reduced GluR1 clusters and protein levels in the hippocampus, and major changes in striatal and corticostriatal synapses [205–207].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [205] Bozdagi O Sakurai T Papapetrou D Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication Mol Autism 2010 1 1 15 21167025 PMC3019144

      Not checked in the free run.

    • cites [206] Peca J Feliciano C Ting JT Shank3 mutant mice display autistic-like behaviours and striatal dysfunction Nature 2011 472 7344 437 42 21423165 PMC3090611

      Not checked in the free run.

    • cites [207] Wang X McCoy PA Rodriguiz RM Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3 Hum Mol Genet 2011 20 15 3093 108 21558424 PMC3131048

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  • May combine two claims.

    Premisecitation

    Mice with heterozygous or homozygous SHANK3 disruption show self-injurious repetitive grooming, social interaction deficits, altered learning and memory, and synaptic transmission defects.

    “Mice with heterozygous or homozygous disruption of SHANK3 have self-injurious repetitive grooming, deficits in social interaction, alterations in learning and memory formation, and defects in synaptic transmission [205–207].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [205] Bozdagi O Sakurai T Papapetrou D Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication Mol Autism 2010 1 1 15 21167025 PMC3019144

      Not checked in the free run.

    • cites [206] Peca J Feliciano C Ting JT Shank3 mutant mice display autistic-like behaviours and striatal dysfunction Nature 2011 472 7344 437 42 21423165 PMC3090611

      Not checked in the free run.

    • cites [207] Wang X McCoy PA Rodriguiz RM Synaptic dysfunction and abnormal behaviors in mice lacking major isoforms of Shank3 Hum Mol Genet 2011 20 15 3093 108 21558424 PMC3131048

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A NLGN3 R451C knock-in mouse has increased inhibitory transmission but no change in excitatory transmission in the somatosensory cortex.

    “A knock-in mouse harboring an autism-associated mutation in a conserved amino acid residue (R451C) of NLGN3 was found have increased inhibitory transmission but no changes in excitatory transmission in the somatosensory cortex [225].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [225] Tabuchi K Blundell J Etherton MR A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice Science 2007 318 5847 71 6 17823315 PMC3235367

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  • May combine two claims.

    Premisecitation

    MeCP2 is a transcriptional regulator highly expressed in GABAergic neurons in the brain.

    “MeCP2 is a transcriptional regulator which is highly expressed in GABAergic neurons in the brain [229]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Akbarian S Chen RZ Gribnau J Expression pattern of the Rett syndrome gene MeCP2 in primate prefrontal cortex Neurobiol Dis 2001 8 5 784 91 11592848

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLGN2-overexpressing mice show stereotyped behavior and impaired social interactions.

    “these mice had stereotypied behavior and impaired social interactions [224].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [224] Hines RM Wu L Hines DJ Synaptic imbalance, stereotypies, and impaired social interactions in mice with altered neuroligin 2 expression J Neurosci 2008 28 24 6055 67 18550748 PMC6670530

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Even slight alterations to NL2 can significantly alter E/I balance and produce particular behavioral deficits.

    “even slight alterations to NL2 can significantly alter E/I balance and result in particular behavioral deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In vitro NL2 over-expression enhances inhibitory circuit transmission, while knockdown decreases it.

    “in vitro NL2 over-expression or knockdown specifically enhanced or decreased inhibitory circuit transmission respectively [188]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [188] Chubykin AA Atasoy D Etherton MR Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2 Neuron 2007 54 6 919 31 17582332 PMC3738748

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both reduced and enhanced expression of ASD genes such as NLs can affect E/I balance, and changes in E/I balance contribute to ASD pathogenesis.

    “these studies provide evidence that both reduced and enhanced expression of ASD genes such as NLs can intimately affect the balance between excitatory and inhibitory transmission, and hence provides strong evidence that a change in the E/I balance contributes to the pathogenesis of ASDs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PTEN deficiency causes hypertrophy of dendritic arbors and increased spine density.

    “PTEN deficiency results in hypertrophy of dendritic arbors and increased spine density [213, 216]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [213] Kwon CH Luikart BW Powell CM Pten regulates neuronal arborization and social interaction in mice Neuron 2006 50 3 377 88 16675393 PMC3902853

      Not checked in the free run.

    • cites [216] Pun RY Rolle IJ Lasarge CL Excessive activation of mTOR in postnatally generated granule cells is sufficient to cause epilepsy Neuron 2012 75 6 1022 34 22998871 PMC3474536

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NL4 is endogenously localized to inhibitory glycinergic synapses in the retina and other CNS areas, associates with gephyrin but not PSD-95 in vivo, and is important for glycinergic-dependent inhibitory transmission in the retina.

    “Hoon et al. [226] showed NL4 was endogenously localized to inhibitory glycinergic synapses in the retina and other areas of the CNS, associates with gephyrin but not PSD-95 in vivo, and is important for glycinergic-dependent inhibitory transmission in the retina.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [226] Hoon M Soykan T Falkenburger B Neuroligin-4 is localized to glycinergic postsynapses and regulates inhibition in the retina Proceedings of the National Academy of Sciences of the United States of America 2011 108 7 3053 8 21282647 PMC3041141

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of FMRP upregulates global dendritic translation rates, which may contribute to elevated spine density in affected individuals.

    “loss of FMRP causes an upregulation in global dendritic translation rates that may contribute to the elevated spine density observed in the brains of affected individuals [217].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [217] Bagni C Greenough WT From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome Nat Rev Neurosci 2005 6 5 376 87 15861180

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A transgenic mouse with an extra copy of NLGN2 has increased inhibitory synapse size and a reduced E/I ratio.

    “a transgenic mouse harboring an extra copy of the NLGN2 gene resulted in increased size of inhibitory synapses and a subsequent reduction in the E/I ratio.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [224] Hines RM Wu L Hines DJ Synaptic imbalance, stereotypies, and impaired social interactions in mice with altered neuroligin 2 expression J Neurosci 2008 28 24 6055 67 18550748 PMC6670530

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The NL2-Nrxn interaction physically links pre- and post-synaptic membranes, regulates pre-synaptic neurotransmitter release, and post-synaptically recruits gephyrin to scaffold GABAA receptors.

    “This interaction provides a physical link between pre- and post-synaptic membranes [158], regulates pre-synaptic neurotransmitter release, and post-synaptically recruits gephyrin which scaffolds GABAA receptors in precise locations [223].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [158] Chih B Gollan L Scheiffele P Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex Neuron 2006 51 2 171 8 16846852

      Not checked in the free run.

    • cites [223] Huang ZJ Scheiffele P GABA and neuroligin signaling: linking synaptic activity and adhesion in inhibitory synapse development Curr Opin Neurobiol 2008 18 1 77 83 18513949 PMC3988756

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  • May combine two claims.

    Premisecitation

    CNTNAP2-knockout mice have reduced PV+ GABAergic interneurons, neuronal synchrony defects, epileptic seizures, and altered social behavior.

    “CNTNAP2-knockout mice have reduced numbers of PV+ GABAergic interneurons, as well as neuronal synchrony defects, epileptic seizures, and altered social behavior [258].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [258] Penagarikano O Abrahams BS Herman EI Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits Cell 2011 147 1 235 46 21962519 PMC3390029

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  • May combine two claims.

    Interpretationcitation

    CNTNAP2 loss may impair connectivity and reduce PV+ interneurons, producing a hyper-excitable network that promotes epileptic symptoms and behavioral abnormalities.

    “CNTNAP2 loss may lead to impairments in connectivity and reductions in the interneuron population, particularly the PV+ subtype, resulting in a hyper-excitable network that promotes downstream epileptic symptoms and behavioral abnormalities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    FMR1 is implicated as an autism susceptibility gene and as a regulator of cortical inhibitory function.

    “thus implicating FMR1 both as an autism susceptibility gene and a regulator of cortical inhibitory function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Active Akt phosphorylates TSC1/TSC2 to disinhibit Rheb, leading to protein translation through mTORC1 phosphorylation of S6K and eIF-4B.

    “Active Akt phosphorylates TSC1/TSC2 to disinhibit Rheb, leading to protein translation through mTOR’s (as a member of mTORC1) phosphorylation of S6 kinase (S6K) and eukaryotic initiation factor (eIF-4B) [268].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [268] Gururajan A van den Buuse M Is the mTOR-signalling cascade disrupted in Schizophrenia? J Neurochem 2014 129 3 377 87 24266366

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    MeCP2 function may be more crucial in some inhibitory circuits than others, and behavioral symptoms may result from region-specific MeCP2-associated defects in GABAergic neurons.

    “these results suggest that MeCP2 function may be more crucial in some inhibitory circuits than others and that behavioral symptoms may be the downstream result of region-specific MeCP2-associated defects in GABAergic neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FMR1 knockout mice have significant reductions and drastic lamina redistributions of PV+ interneurons in the neocortex but not the hippocampus.

    “knockout mice have significant reductions and drastic lamina redistributions of PV+ interneurons in the neocortex, but not hippocampus”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [246] Selby L Zhang C Sun QQ Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation protein Neurosci Lett 2007 412 3 227 32 17197085 PMC1839948

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CNTNAP2 knockdown reduces dendrite arborization and impairs synaptic transmission in mouse cortical neurons.

    “CNTNAP2 knockdown led to decreases in dendrite arborization and impaired synaptic transmission in mouse cortical neurons [257].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [257] Anderson GR Galfin T Xu W Aoto J Malenka RC Sudhof TC Candidate autism gene screen identifies critical role for cell-adhesion molecule CASPR2 in dendritic arborization and spine development Proceedings of the National Academy of Sciences of the United States of America 2012 109 44 18120 5 23074245 PMC3497786

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with MECP2 deletion from forebrain GABAergic interneurons exhibit repetitive behaviors, increased sociability, cognitive deficits, impaired motor coordination, and neuronal hyperexcitability.

    “mice with specific deletion of MECP2 from forebrain GABAergic-interneurons exhibit repetitive behaviors, increased sociability, cognitive deficits, impaired motor coordination and neuronal hyperexcitability [233].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Chao HT Chen H Samaco RC Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes Nature 2010 468 7321 263 9 21068835 PMC3057962

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning

    Phosphorylation of TSC1/TSC2 causes dissociation and activates Rheb.

    “Phosphorylation of TSC1/TSC2 dissociates with and thereby activates Rheb.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    mTOR is controlled by TSC1/TSC2, which binds and constitutively inhibits Rheb, a direct mTOR activator.

    “mTOR is controlled by the tuberous sclerosis complex (TSC1/TSC2), a heteromer which binds and constitutively inhibits the GTPase Ras-homolog enriched in brain (Rheb), a direct activator of mTOR.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CNTNAP2 is expressed at ganglionic eminences during development and interacts with TAG-1, a protein involved in interneuron migration.

    “CNTNAP2 is expressed at the ganglionic eminences during development [258] and interacts to TAG-1 [259], a protein involved in interneuron migration [260].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [258] Penagarikano O Abrahams BS Herman EI Absence of CNTNAP2 leads to epilepsy, neuronal migration abnormalities, and core autism-related deficits Cell 2011 147 1 235 46 21962519 PMC3390029

      Not checked in the free run.

    • cites [259] Traka M Goutebroze L Denisenko N Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers J Cell Biol 2003 162 6 1161 72 12975355 PMC2172849

      Not checked in the free run.

    • cites [260] Denaxa M Chan CH Schachner M Parnavelas JG Karagogeos D The adhesion molecule TAG-1 mediates the migration of cortical interneurons from the ganglionic eminence along the corticofugal fiber system Development 2001 128 22 4635 44 11714688

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Activated PI3K promotes Akt activation via PIP3 production, while PTEN opposes PI3K by depleting PIP3.

    “Activated PI3K promotes plasma membrane translocation and subsequent activation of Protein Kinase B (Akt) via production of phosphatidylinositol (3,4,5)- triphosphate (PIP3); meanwhile, PTEN opposes PI3K by depleting PIP3.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BDNF regulates development and maturation of inhibitory circuits and is a MeCP2 target.

    “brain-derived neurotrophic factor (BDNF), which regulates development and maturation of inhibitory circuits in the brain, is a MeCP2 target [237].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Martinowich K Hattori D Wu H DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation Science 2003 302 5646 890 3 14593184

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    FXS mice are useful models for analyzing how FMRP links region-specific GABA dysregulation to autistic symptoms, but caution is needed because FXS is not pure autism.

    “FXS mice are good animal models analyze how FMRP links region-specific GABA dysregulation to autistic symptoms; however, caution must be taken as that FXS is not a “pure” autism and thus cannot entirely be relied upon to understand the latter’s complex pathophysiology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CNTNAP2 is a neurexin cell-adhesion molecule highly expressed throughout the CNS, with highest expression in frontal and anterior lobes, striatum, and dorsal thalamus.

    “Contactin-associated protein-like 2 (CNTNAP2) is a neurexin cell-adhesion molecule that is highly expressed throughout the central nervous system, with highest expression in the frontal and anterior lobes, striatum and dorsal thalamus [256]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [256] Alarcon M Abrahams BS Stone JL Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene Am J Hum Genet 2008 82 1 150 9 18179893 PMC2253955

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisereasoning

    In the PI3K-Akt-mTOR pathway, extracellular factors binding to receptors activate PI3K at the plasma membrane.

    “binding of various extracellular factors (mitogens, trophic factors, and glutamate) to respective receptors lead to the activation of phosphatidylinositol 3-kinase (PI3K) at the plasma membrane.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    This discovery may have joined two previously disparate pathways.

    “this discovery may have joined two previously disparate pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    NMDAR dysfunction could be a convergence point in ASD and SCZ pathophysiology and may drive disease progression in both disorders.

    “NMDAR dysfunction could be a convergence point in ASD and SCZ pathophysiology and may be responsible for disease progression in both disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    DISC1 knockdown in adult-born dentate gyrus neurons accelerates dendrite development, causes network hyperexcitability, and increases phosphorylated Akt.

    “DISC1 knockdown of adult-born neurons in the dentate gyrus led to acceleration of dendrite development, network hyperexcitability, and an increase in phosphorylated Akt.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Lymphoblast lines from SCZ patients have upregulated ErbB4 CYT-1, which contains a PI3K-binding site and triggers PI3K pathway activation.

    “Lymphoblast lines from schizophrenic patients have upregulated expression of the ErbB4 receptor isoform CYT-1, which contains a PI3K-binding site and triggers activation of the PI3K pathway [280, 281].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [280] Junttila TT Sundvall M Maatta JA Elenius K Erbb4 and its isoforms: selective regulation of growth factor responses by naturally occurring receptor variants Trends Cardiovasc Med 2000 10 7 304 10 11343971

      Not checked in the free run.

    • cites [281] Law AJ Wang Y Sei Y Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110delta inhibition as a potential therapeutic strategy Proceedings of the National Academy of Sciences of the United States of America 2012 109 30 12165 70 22689948 PMC3409795

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    mTOR regulates cell proliferation, growth, and synaptogenesis.

    “mTOR regulates a variety of neuronal functions, including cell proliferation, growth, and synaptogenesis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Loss of FMRP results in enhanced mTOR signaling and increased eIF4F formation in a mouse model of FXS.

    “loss of FMRP resulted in enhanced mTOR signaling and subsequent increased formation of the eukaryotic initiation factor complex 4F (eIF4F) in a mouse model of FXS [290].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [290] Sharma A Hoeffer CA Takayasu Y Dysregulation of mTOR signaling in fragile X syndrome J Neurosci 2010 30 2 694 702 20071534 PMC3665010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DISC1 interacts with and suppresses KIAA1212, an Akt signaling enhancer.

    “DISC1 interacts with and suppressed KIAA1212, an Akt signaling enhancer”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [261] Kim JY Duan X Liu CY DISC1 regulates new neuron development in the adult brain via modulation of AKT-mTOR signaling through KIAA1212 Neuron 2009 63 6 761 73 19778506 PMC3075620

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hippocampal TSC1-knockout neurons exhibit mTOR hyperactivity, decreased inhibitory transmission, no change in excitatory transmission, network hyperexcitability, and normal spine density and size.

    “Hippocampal TSC1-knockout neurons exhibited mTOR hyperactivity, decreased inhibitory transmission (yet no changes in excitatory transmission), and network hyperexcitability [47] but normal spine density and size [288].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Bateup HS Johnson CA Denefrio CL Saulnier JL Kornacker K Sabatini BL Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis Neuron 2013 78 3 510 22 23664616 PMC3690324

      Not checked in the free run.

    • cites [288] Bateup HS Takasaki KT Saulnier JL Denefrio CL Sabatini BL Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function J Neurosci 2011 31 24 8862 9 21677170 PMC3133739

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    NMDARs are tetrameric, containing two NR1 subunits and either two NR2 or two NR3 subunits.

    “Structurally tetrameric, they contain two NR1 obligatory subunits and either two NR2 (A, B, C or D) or two NR3 (A or B) subunits”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Targeted inhibition of p110δ increases Akt Thr308 phosphorylation and reverses PPI deficits in a neurodevelopmental rat model of SCZ.

    “targeted inhibition of p110δ increased Akt Thr308 phosphorylation and reversed PPI deficits in a neurodevelopmental rat model of SCZ [281]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [281] Law AJ Wang Y Sei Y Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110delta inhibition as a potential therapeutic strategy Proceedings of the National Academy of Sciences of the United States of America 2012 109 30 12165 70 22689948 PMC3409795

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NMDARs are predominant molecular devices for controlling experience-dependent synaptic remodeling and long-lasting synaptic changes, crucial for associative learning, working memory, behavioral flexibility, and attention.

    “make NMDARs the predominant molecular devices for controlling complex experience-dependent synaptic remodeling and long-lasting synaptic changes, which are crucial for associative learning, working memory, behavioral flexibility or attention [297].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [297] Lisman J Schulman H Cline H The molecular basis of CaMKII function in synaptic and behavioural memory Nat Rev Neurosci 2002 3 3 175 90 11994750

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with dentate gyrus-specific DISC1 knockdown exhibit schizophrenia-like symptoms including cognitive deficits and anxiety, and rapamycin injection rescues these defects in a time-sensitive manner.

    “mice with dentate gyrus-specific DISC1 knockdown exhibited schizophrenic-like symptoms including cognitive deficits and anxiety, but rapamycin injection was able to rescue these defects in a time-sensitive manner [278].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [278] Zhou M Li W Huang S mTOR Inhibition ameliorates cognitive and affective deficits caused by Disc1 knockdown in adult-born dentate granule neurons Neuron 2013 77 4 647 54 23439118 PMC3586374

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dysregulation of these processes can impact channel function and expression and alter synaptic transmission.

    “Dysregulation of these processes can impact channel function and expression and alter synaptic transmission [298, 299].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [298] Lau CG Zukin RS NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders Nat Rev Neurosci 2007 8 6 413 26 17514195

      Not checked in the free run.

    • cites [299] Gladding CM Raymond LA Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function Mol Cell Neurosci 2011 48 4 308 20 21600287

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NRG-1 induces phosphorylation of ErbB4 receptors, which become docking sites for upstream mTOR molecules such as PI3K.

    “NRG-1 induces the phosphorylation of the ErbB4 receptors, which then become docking sites for upstream mTOR molecules such as PI3K [279].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [279] Fuller SJ Sivarajah K Sugden PH ErbB receptors, their ligands, and the consequences of their activation and inhibition in the myocardium J Mol Cell Cardiol 2008 44 5 831 54 18430438

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Removal of TSC1 throughout the cortex, subcortical gray matter, and hippocampal CA3 and hilar neurons produces spontaneous seizures by day 5 and death within 3-5 weeks.

    “removal of TSC1 throughout the cortex, subcortical gray matter, and hippocampal CA3 and hilar neurons produced mice with spontaneous seizures by day 5 and death within 3–5 weeks [287].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [287] Meikle L Talos DM Onda H A mouse model of tuberous sclerosis: neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival J Neurosci 2007 27 21 5546 58 17522300 PMC6672762

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of PTEN hyperactivates mTOR, enhances both excitatory and inhibitory neurotransmission in the hippocampus, and increases spine density.

    “Loss of PTEN hyperactivated mTOR, but surprisingly also enhanced both excitatory and inhibitory neurotransmission in the hippocampus [289] and increased spine density [213].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [289] Weston MC Chen H Swann JW Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures Front Mol Neurosci 2014 7 1 24574959 PMC3922082

      Not checked in the free run.

    • cites [213] Kwon CH Luikart BW Powell CM Pten regulates neuronal arborization and social interaction in mice Neuron 2006 50 3 377 88 16675393 PMC3902853

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NMDARs exist as multiple subtypes with unique physiological and pharmacological properties and are spatially and developmentally regulated and differentially distributed across neuronal subtypes.

    “NMDARs exist as multiple subtypes - with each having uniquely physiological and pharmacological properties - and are spatially and developmentally regulated and differentially distributed across neuronal subtypes [296].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [296] Paoletti P Bellone C Zhou Q NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease Nat Rev Neurosci 2013 14 6 383 400 23686171

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Macrocephaly and epilepsy are observed in 10-30% of patients with ASD.

    “observations of macrocephaly and epilepsy in 10–30% of the patients with ASD [286].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [286] Bourgeron T A synaptic trek to autism Curr Opin Neurobiol 2009 19 2 231 4 19545994

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    A prominent hypothesis proposes that NMDARs on PV+ neurons are hypofunctional, causing lowered GABAergic signaling, overstimulation of excitatory neurons, and loss of gamma wave oscillations.

    “A prominent hypothesis for SCZ pathophysiology posits that NMDARs on PV+ neurons are hypofunctional, thus resulting in lowered GABAergic signaling, overstimulation of excitatory neurons, and a consequent loss of gamma wave oscillations [58].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Gonzalez-Burgos G Lewis DA GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia Schizophr Bull 2008 34 5 944 61 18586694 PMC2518635

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A MECP2-overexpression mouse has elevated mTOR signaling, while a MECP2-knockout model shows the opposite effects.

    “a MECP2-overexpression mouse also has elevated mTOR signaling [291] while a MECP2-knockout model displays the opposite effects [292].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [291] Jiang M Ash RT Baker SA Dendritic arborization and spine dynamics are abnormal in the mouse model of MECP2 duplication syndrome J Neurosci 2013 33 50 19518 33 24336718 PMC3858623

      Not checked in the free run.

    • cites [292] Ricciardi S Boggio EM Grosso S Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model Hum Mol Genet 2011 20 6 1182 96 21212100

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Dysbindin-1 over-expression in cortical neurons is neuroprotective against apoptosis via PI3K/Akt activation, while knockdown has the opposite effect.

    “over-expression of dysbindin-1 in cortical neurons has a neuroprotective effect against apoptosis via PI3K/Akt pathway activation while knockdown has the opposite effect [285].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [285] Numakawa T Yagasaki Y Ishimoto T Evidence of novel neuronal functions of dysbindin, a susceptibility gene for schizophrenia Hum Mol Genet 2004 13 21 2699 708 15345706

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    NMDARs are ionotropic glutamate receptors essential for ion flux and positioned to control E/I balance at the synaptic level.

    “N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors essential for mediating ion flux and hence are clearly positioned to control E/I balance at the synaptic level.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NRG1-ErbB4 and PI3K-Akt are involved in neural circuit development and synaptic plasticity.

    “NRG1-ErbB4 and PI3K-Akt are involved in neural circuit development and synaptic plasticity [87, 284]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [87] Fazzari P Paternain AV Valiente M Control of cortical GABA circuitry development by Nrg1 and ErbB4 signalling Nature 2010 464 7293 1376 80 20393464

      Not checked in the free run.

    • cites [284] Cuesto G Enriquez-Barreto L Carames C Phosphoinositide-3-kinase activation controls synaptogenesis and spinogenesis in hippocampal neurons J Neurosci 2011 31 8 2721 33 21414895 PMC6623769

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chronic MK-801 treatment in rats enhances ErbB4 association with PSD-95 and increases ErbB4 phosphorylation.

    “chronic MK-801 treatment in rats enhanced ErbB4’s association with PSD-95 and increased ErbB4’s phosphorylation levels [313].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [313] Li JT Feng Y Su YA Wang XD Si TM Enhanced interaction among ErbB4, PSD-95 and NMDAR by chronic MK-801 treatment is associated with behavioral abnormalities Pharmacol Biochem Behav 2013 108 44 53 23603030

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A possible interaction between NL1 and NMDARs is mediated by PSD-95 through the C-terminal PDZ domain of NL1.

    “NL1 may interact with NMDARs through PSD-95 via its C-terminal PDZ domain [331]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [331] Irie M Hata Y Takeuchi M Binding of neuroligins to PSD-95 Science 1997 277 5331 1511 5 9278515

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This suggests NL1 is needed for NMDAR-mediated currents, normal LTP, and specific behavioral tasks.

    “suggesting NL1 is required for NMDAR-mediated currents, normal LTP function, and specific behavioral tasks.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Blundell J Blaiss CA Etherton MR Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior J Neurosci 2010 30 6 2115 29 20147539 PMC2824441

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shank3 is a scaffold protein that traffics NMDARs to synapses.

    “Shank3 - a scaffold protein which acts to traffic NMDAR to synapses”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [327] Duffney LJ Wei J Cheng J Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism J Neurosci 2013 33 40 15767 78 24089484 PMC3787498

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NL1-PSD95 interactions are neither necessary nor sufficient for recruiting NMDARs to postsynaptic sites.

    “A recent study showed NL1-PSD95 interactions to be neither necessary nor sufficient for NMDARs recruitment to postsynaptic sites”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [330] Budreck EC Kwon OB Jung JH Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling Proceedings of the National Academy of Sciences of the United States of America 2013 110 2 725 30 23269831 PMC3545745

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both deficits are rescued by the NMDAR partial agonist D-cycloserine or by boosting NMDAR activity with an mGluR5 positive allosteric modulator.

    “both deficits are rescued with NMDAR partial agonist D-cycloserine or through enhancement of NMDAR activity via a positive allosteric modulator of mGluR5 [209].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [209] Won H Lee HR Gee HY Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function Nature 2012 486 7402 261 5 22699620

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Shank3 knockdown effect is blocked by an actin stabilizer and mimicked by an actin destabilizer or a Rac1/PAK inhibitor.

    “This effect was blocked by an actin stabilizer but mimicked with an actin destabilizer and a Rac1 or PAK inhibitor [327]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [327] Duffney LJ Wei J Cheng J Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism J Neurosci 2013 33 40 15767 78 24089484 PMC3787498

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ErbB4 is enriched in the PSD, and its association with PSD-95 enhances NRG1-dependent signaling.

    “ErbB4 is enriched in the PSD and its association with PSD-95 results in enhancement of NRG1-dependent signaling [83].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [83] Huang YZ Won S Ali DW Regulation of neuregulin signaling by PSD-95 interacting with ErbB4 at CNS synapses Neuron 2000 26 2 443 55 10839362

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationcitation

    The regional differences in RTT mice agree with those postmortem binding findings.

    “which is also consistent with previous postmortem binding studies showing significant alterations in total NMDA receptor complexes only in particular regions of the Rett syndrome brain [336, 337].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [336] Blue ME Naidu S Johnston MV Development of amino acid receptors in frontal cortex from girls with Rett syndrome Ann Neurol 1999 45 4 541 5 10211484

      Not checked in the free run.

    • cites [337] Blue ME Naidu S Johnston MV Altered development of glutamate and GABA receptors in the basal ganglia of girls with Rett syndrome Exp Neurol 1999 156 2 345 52 10328941

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MECP2-null mice have lower overall NR2A/NR2B ratios and NR1 levels at synapses than wildtype.

    “MECP2-null mice to have decreases in overall NR2A/NR2B ratio and NR1 levels at the synapses compared to wildtype [332]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [332] Maliszewska-Cyna E Bawa D Eubanks JH Diminished prevalence but preserved synaptic distribution of N-methyl-D-aspartate receptor subunits in the methyl CpG binding protein 2(MeCP2)-null mouse brain Neuroscience 2010 168 3 624 32 20381590

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SHANK2 mutant mice display autistic-like behaviors and reduced functional NMDARs.

    “SHANK2 mutant mice have autistic-like behaviors and decreased functional NMDARs”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [209] Won H Lee HR Gee HY Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function Nature 2012 486 7402 261 5 22699620

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    These changes align with delayed synaptic maturation and fewer functional NMDA receptors.

    “which is consistent with attenuated synaptic maturation [333, 334] and fewer overall functional NMDA receptors respectively”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [333] Townsend M Yoshii A Mishina M Constantine-Paton M Developmental loss of miniature N-methyl-D-aspartate receptor currents in NR2A knockout mice Proceedings of the National Academy of Sciences of the United States of America 2003 100 3 1340 5 12552130 PMC298774

      Not checked in the free run.

    • cites [334] Fu Z Logan SM Vicini S Deletion of the NR2A subunit prevents developmental changes of NMDA-mEPSCs in cultured mouse cerebellar granule neurones J Physiol 2005 563 Pt 3 867 81 15649973 PMC1665615

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLGN1-knockout mice show spatial learning and memory deficits and repetitive behavior, along with impaired hippocampal LTP and a lower NMDA/AMPA ratio.

    “NLGN1-knockout mice have deficits in spatial learning and memory as well as repetitive behavior, which corresponded with impaired hippocampal LTP and decreased NMDA/AMPA ratio [192].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [192] Blundell J Blaiss CA Etherton MR Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior J Neurosci 2010 30 6 2115 29 20147539 PMC2824441

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A PV-specific GRIN1-knockout mouse model displays pyramidal cell hyperexcitability, neural synchrony reductions, and schizophrenia-like behaviors.

    “a PV-specific GRIN1-knockout mouse model displaying pyramidal cell hyperexcitability, neural synchrony reductions, and schizophrenic-like behaviors [306].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [306] Belforte JE Zsiros V Sklar ER Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes Nat Neurosci 2010 13 1 76 83 19915563 PMC2797836

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Bath perfusion of mouse PFC slices with NRG1 decreases NMDAR-mediated EPSCs via internalization of the NR1 subunit, and this effect is blocked by ErbB4 inhibitors.

    “bath perfusion of mouse prefrontal cortex (PFC) brain slices with NRG1 decreased NMDAR-mediated EPSCs via internalization of the NR1 subunit, with this effect being blocked by ErbB4 inhibitors [312].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [312] Gu Z Jiang Q Fu AK Ip NY Yan Z Regulation of NMDA receptors by neuregulin signaling in prefrontal cortex J Neurosci 2005 25 20 4974 84 15901778 PMC6724849

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The finding was verified with immunoelectron microscopy and an MK-801 wash-out paradigm.

    “This was verified using immunoelectron microscopy images and with a MK-801 wash-out paradigm [330].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [330] Budreck EC Kwon OB Jung JH Neuroligin-1 controls synaptic abundance of NMDA-type glutamate receptors through extracellular coupling Proceedings of the National Academy of Sciences of the United States of America 2013 110 2 725 30 23269831 PMC3545745

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PMDS patient-derived iPSC neurons show reduced Shank3 expression and major excitatory transmission defects, partly due to fewer NMDA receptors and excitatory synapses.

    “patients had reduced Shank3 expression and major defects in excitatory transmission due partially to decreased NMDA receptors and reduced excitatory synapses”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [328] Shcheglovitov A Shcheglovitova O Yazawa M SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients Nature 2013 503 7475 267 71 24132240 PMC5559273

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The lower ratio leads to impaired CA1 long-term potentiation and poorer spatial learning and memory that depend on the hippocampus.

    “leading to reduced CA1 LTP, and deficits in hippocampus-dependent spatial learning and memory [329].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [329] Kouser M Speed HE Dewey CM Loss of predominant Shank3 isoforms results in hippocampus-dependent impairments in behavior and synaptic transmission J Neurosci 2013 33 47 18448 68 24259569 PMC3834052

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cultured neurons, Shank3 knockdown lowers NMDAR-mediated synaptic currents and reduces NR1 surface expression.

    “RNAi knockdown of Shank3 in culture leads to reduction of NMDAR-mediated synaptic current as well as loss of NR1 surface expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [327] Duffney LJ Wei J Cheng J Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism J Neurosci 2013 33 40 15767 78 24089484 PMC3787498

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A large study from the Consortium on the Genetics of Schizophrenia verified the connection and discovered genes encoding NR1 interacting proteins associated with SCZ.

    “a recent large study from the Consortium on the Genetics of Schizophrenia verified this connection and also discovered several genes encoding for NR1 interacting proteins associated with the disease [309].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [309] Greenwood TA Lazzeroni LC Murray SS Analysis of 94 candidate genes and 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia Am J Psychiatry 2011 168 9 930 46 21498463 PMC3751972

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMR1-knockout mice have reduced LTP and a lower NMDA/AMPA ratio in the dentate gyrus.

    “FMR1-knockout mice had diminished LTP and lowered NMDA/AMPA ratio in the dentate gyrus (DG)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [340] Eadie BD Cushman J Kannangara TS Fanselow MS Christie BR NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice Hippocampus 2012 22 2 241 54 21049485

      Not checked in the free run.

124 of 124

  • The paper relies on this without support.

    Behavioral phenotypes in rodent models described as schizophrenia-like or autism-like correspond to the human disorders.

    “mice lacking ErbB4 in the CNS show reduced spine density in both the hippocampus and cortex and exhibit schizophrenia-related behavioral phenotypes [84].”

  • The paper relies on this without support.

    Postmortem brain findings reflect antemortem pathophysiological processes relevant to the disease.

    “Postmortem studies have examined brain regions showing the highest indices of gray matter loss and have consistently found reductions in spine density in these parts.”

  • The paper relies on this without support.

    Spine density changes observed in animal models are relevant to human SCZ and ASD pathophysiology.

    “Primary hippocampal neurons from mice engineered to carry hemizygous deletion of the 1.3-Mb orthologous chromosomal region (Df(16)A+/−) showed reduced spine density and sizes [107].”

  • The paper relies on this without support.

    A significant symptom overlap exists between ASD and SCZ.

    “a significant overlap in symptoms exists”

  • The paper relies on this without support.

    FXS, like many developmental disorders, involves synaptic plasticity changes that may impair learning and memory.

    “Like many developmental disorders, FXS is associated with alterations in synaptic plasticity that may impair learning and memory processes in the brain.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Dysfunction and/or deficient inhibitory output from PV interneurons may be a common mechanism of multiple psychiatric disorders, such as schizophrenia, autism spectrum disorders and bipolar disorder.

    “Dysfunction and/or deficient inhibitory output from PV interneurons may be a common mechanism of multiple psychiatric disorders, such as schizophrenia (SCZ) (Lewis et al. 2005), autism spectrum disorders (ASD) (Gao and Penzes 2015) and bipolar disorder (BD) (Ruden et al. 2021).”

    From Neuronal pentraxins as biomarkers of synaptic activity: from physiological functions to pathological changes in neurodegeneration (2022) · cites this paper as Gao and Penzes 2015

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Authors
Gao, R., & Penzes, P.
Affiliations
Northwestern University (US)
ORCID
Penzes, P.
Venue
Current Molecular Medicine
Publisher
Bentham Science Publishers Ltd.
Published
2015-03-18
Volume
15
Issue
2
Pages
146-167
ISSN
1566-5240 (ISSN-L)
DOI
10.2174/1566524015666150303003028
PMC
PMC4721588
OpenAlex
W2334244908
Semantic Scholar
b6b53ecd1928312e333aef0b5f5b4a187daf721f
Cited by
516
References
339
Citations by year
2026: 27 · 2025: 53 · 2024: 51 · 2023: 57 · 2022: 59 · 2021: 75 · 2020: 66 · 2019: 39 · 2018: 42 · 2017: 32 · 2016: 11 · 2015: 4
FWCI
13.84
Type
journal article
Language
en
Open access
Locations
  • Current Molecular Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Mental Health (F30MH096457, R01MH071316)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
excitatory-inhibitory imbalance, schizophrenia, autism spectrum disorder, shared pathophysiology, glutamatergic circuits, inhibitory interneurons, genetic architecture, neuropathology, therapeutic target
MeSH terms
Autism Spectrum Disorder, Gene Expression Regulation, Humans, Interneurons, Nerve Tissue Proteins, Synaptic Transmission, Schizophrenia, Synapses, Receptors, N-Methyl-D-Aspartate, Pyramidal Cells, Genetic Predisposition to Disease, Dendritic Spines, TOR Serine-Threonine Kinases, GABAergic Neurons

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-07.

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