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

In the paper

“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].”

What the sources say

• Not checked yetcites [6] Rapin I Tuchman RF Autism: definition, neurobiology, screening, diagnosis Pediatr Clin North Am 2008 55 5 1129 46 viii 18929056
• Not checked yetcites [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

In the paper

“Autism Spectrum Disorders (ASD) and Schizophrenia (SCZ) are two highly heritable spectrum disorders with complicated genetic etiologies but overlapping behavioral phenotypes [1].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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]”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“NRG1 and ERBB4 are two of the most reproducible SCZ candidate genes [69–76].”

What the sources say

• Not checked yetcites [69] Stefansson H Sigurdsson E Steinthorsdottir V Neuregulin 1 and susceptibility to schizophrenia Am J Hum Genet 2002 71 4 877 92 12145742 PMC378543
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [72] Munafo MR Attwood AS Flint J Neuregulin 1 genotype and schizophrenia Schizophr Bull 2008 34 1 9 12 18032396 PMC2632377
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [15] Fritschy JM Brunig I Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications Pharmacol Ther 2003 98 3 299 323 12782242

In the paper

“Long-term NRG1 treatment increases pyramidal neuronal spine density and the preponderance of spines with mature phenotypes [84]”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [49] Zoghbi HY Postnatal neurodevelopmental disorders: meeting at the synapse? Science 2003 302 5646 826 30 14593168
• Not checked yetcites [50] Fatemi SH Folsom TD The neurodevelopmental hypothesis of schizophrenia, revisited Schizophr Bull 2009 35 3 528 48 19223657 PMC2669580

In the paper

“Similarly, ErbB4 over-expression increases spine density, area, and excitatory synaptic transmission while ErbB4 knockdown reduces spine density and size [86].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [64] Lewis DA Hashimoto T Volk DW Cortical inhibitory neurons and schizophrenia Nat Rev Neurosci 2005 6 4 312 24 15803162
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“DTNBP1-knockout mice have reductions in the excitability of cortical and striatal PV+ interneurons, which in turn lead to hyperexcitable pyramidal cells [134].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [100] Meyer KD Morris JA Disc1 regulates granule cell migration in the developing hippocampus Hum Mol Genet 2009 18 17 3286 97 19502360 PMC2722990
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“More specifically, ErbB4 is expressed in nearly all PV+ interneurons in the neocortex [120] and over half in the hippocampus [123].”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [108] Engel AK Singer W Temporal binding and the neural correlates of sensory awareness Trends Cogn Sci 2001 5 1 16 25 11164732
• Not checked yetcites [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 yetcites [109] Herrmann CS Demiralp T Human EEG gamma oscillations in neuropsychiatric disorders Clin Neurophysiol 2005 116 12 2719 33 16253555
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Early brain overgrowth and neuronal hyperexcitability are two well-established phenotypes in ASD [135, 136].”

What the sources say

• Not checked yetcites [135] Parellada M Penzol MJ Pina L The neurobiology of autism spectrum disorders Eur Psychiatry 2014 29 1 11 9 24275633
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Finally, a KALRN-knockout mouse shows severe reductions in spine density in the frontal cortex and schizophrenic-like behaviors during adolescent years [105].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“For instance, the fragile X brain is characterized by macrocephaly, elevated spine density and elongated, tortuous spine morphologies [139].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“while 30% struggle with epilepsy [138].”

What the sources say

• Not checked yetcites [138] Tuchman R Rapin I Epilepsy in autism Lancet Neurol 2002 1 6 352 8 12849396

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [159] Missler M Zhang W Rohlmann A Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis Nature 2003 423 6943 939 48 12827191
• Not checked yetcites [160] Varoqueaux F Aramuni G Rawson RL Neuroligins determine synapse maturation and function Neuron 2006 51 6 741 54 16982420

In the paper

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

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [154] Sudhof TC Neuroligins and neurexins link synaptic function to cognitive disease Nature 2008 455 7215 903 11 18923512 PMC2673233
• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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
• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“α-NRXN1-knockout mice have hippocampal E/I imbalance due to decreased spontaneous excitatory post-synaptic currents and decreased prepulse inhibitions”

What the sources say

• Not checked yetcites [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

In the paper

“SHANK1-knockout mice have small dendritic spines, weakened synaptic transmission [203], and defects in social communication [204].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [227] Chahrour M Zoghbi HY The story of Rett syndrome: from clinic to neurobiology Neuron 2007 56 3 422 37 17988628
• Not checked yetcites [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

In the paper

“each of these proteins regulates synaptic structure [213–215].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“while NL3 is predominantly localized to excitatory synapses [184], it is also found to a lesser extent in GABAergic synapses [183].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“MeCP2 is a transcriptional regulator which is highly expressed in GABAergic neurons in the brain [229]”

What the sources say

• Not checked yetcites [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

In the paper

“these mice had stereotypied behavior and impaired social interactions [224].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“in vitro NL2 over-expression or knockdown specifically enhanced or decreased inhibitory circuit transmission respectively [188]”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“PTEN deficiency results in hypertrophy of dendritic arbors and increased spine density [213, 216]”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“CNTNAP2-knockout mice have reduced numbers of PV+ GABAergic interneurons, as well as neuronal synchrony defects, epileptic seizures, and altered social behavior [258].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“thus implicating FMR1 both as an autism susceptibility gene and a regulator of cortical inhibitory function.”

In the paper

“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].”

What the sources say

• Not checked yetcites [268] Gururajan A van den Buuse M Is the mTOR-signalling cascade disrupted in Schizophrenia? J Neurochem 2014 129 3 377 87 24266366

In the paper

“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.”

In the paper

“knockout mice have significant reductions and drastic lamina redistributions of PV+ interneurons in the neocortex, but not hippocampus”

What the sources say

• Not checked yetcites [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

In the paper

“CNTNAP2 knockdown led to decreases in dendrite arborization and impaired synaptic transmission in mouse cortical neurons [257].”

What the sources say

• Not checked yetcites [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

In the paper

“mice with specific deletion of MECP2 from forebrain GABAergic-interneurons exhibit repetitive behaviors, increased sociability, cognitive deficits, impaired motor coordination and neuronal hyperexcitability [233].”

What the sources say

• Not checked yetcites [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

In the paper

“Phosphorylation of TSC1/TSC2 dissociates with and thereby activates Rheb.”

In the paper

“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.”

In the paper

“CNTNAP2 is expressed at the ganglionic eminences during development [258] and interacts to TAG-1 [259], a protein involved in interneuron migration [260].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“brain-derived neurotrophic factor (BDNF), which regulates development and maturation of inhibitory circuits in the brain, is a MeCP2 target [237].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“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]”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“this discovery may have joined two previously disparate pathways.”

In the paper

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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“mTOR regulates a variety of neuronal functions, including cell proliferation, growth, and synaptogenesis”

In the paper

“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].”

What the sources say

• Not checked yetcites [290] Sharma A Hoeffer CA Takayasu Y Dysregulation of mTOR signaling in fragile X syndrome J Neurosci 2010 30 2 694 702 20071534 PMC3665010

In the paper

“DISC1 interacts with and suppressed KIAA1212, an Akt signaling enhancer”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“Structurally tetrameric, they contain two NR1 obligatory subunits and either two NR2 (A, B, C or D) or two NR3 (A or B) subunits”

In the paper

“targeted inhibition of p110δ increased Akt Thr308 phosphorylation and reversed PPI deficits in a neurodevelopmental rat model of SCZ [281]”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“Dysregulation of these processes can impact channel function and expression and alter synaptic transmission [298, 299].”

What the sources say

• Not checked yetcites [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 yetcites [299] Gladding CM Raymond LA Mechanisms underlying NMDA receptor synaptic/extrasynaptic distribution and function Mol Cell Neurosci 2011 48 4 308 20 21600287

In the paper

“NRG-1 induces the phosphorylation of the ErbB4 receptors, which then become docking sites for upstream mTOR molecules such as PI3K [279].”

What the sources say

• Not checked yetcites [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