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Cited by 1,523Neuroscience and Neuropharmacology ResearchGenetics and Neurodevelopmental DisordersAutism Spectrum Disorder Research

Dendritic spine pathology in neuropsychiatric disorders

Open access
Penzes, Peter, Cahill, Michael E, Jones, Kelly A, VanLeeuwen, Jon-Eric, Woolfrey, Kevin M·2011·Nature Neuroscience
DOI 10.1038/nn.2741PMC PMC3530413
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Abstract

Substantial progress has been made toward understanding the genetic architecture, cellular substrates, brain circuits and endophenotypic profiles of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia and Alzheimer's disease. Recent evidence implicates spiny synapses as important substrates of pathogenesis in these disorders. Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of spine pathology may provide insight into their etiologies and may reveal new drug targets. Here we discuss recent neuropathological, genetic, molecular and animal model studies that implicate structural alterations at spiny synapses in the pathogenesis of major neurological disorders, focusing on ASD, schizophrenia and Alzheimer's disease as representatives of these categories across different ages of onset. We stress the importance of reverse translation, collaborative and multidisciplinary approaches, and the study of the spatio-temporal roles of disease molecules in the context of synaptic regulatory pathways and neuronal circuits that underlie disease endophenotypes.

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  • Premisecitation

    A reduction in superior temporal gyrus gray matter volume is one of the most consistently reported alterations in schizophrenia.

    “A reduction in superior temporal gyrus gray matter volume is one of the most consistently reported alterations in the schizophrenia brain14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Yoshida, T. et al. A prospective longitudinal volumetric MRI study of superior temporal gyrus gray matter and amygdala-hippocampal complex in chronic schizophrenia. Schizophr. Res. 113, 84–94 (2009). source

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  • Premisecitation

    Individuals with schizophrenia show a profound reduction in spine density on pyramidal neurons in the superior temporal gyrus, particularly in the primary auditory cortex.

    “At the cellular level, individuals with schizophrenia show a profound reduction in spine density on pyramidal neurons in the superior temporal gyrus, particularly in the primary auditory cortex15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Sweet, R.A., Henteleff, R.A., Zhang, W., Sampson, A.R. & Lewis, D.A. Reduced dendritic spine density in auditory cortex of subjects with schizophrenia. Neuropsychopharmacology 34, 374–389 (2009). source

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  • Premisecitation

    Postmortem tissue from patients with Alzheimer's disease consistently shows prominent synapse loss.

    “Studies analyzing postmortem tissue samples from patients diagnosed with Alzheimer’s disease consistently report prominent synapse loss7,18.”
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    • cites [7] Selkoe, D.J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002). source

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    • cites [18] DeKosky, S.T. & Scheff, S.W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464 (1990). source

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  • Interpretationreasoning

    In schizophrenia, brain region-specific gray matter loss, reduced spine density, and functional hypoactivity are strongly associated.

    “Collectively, these studies reveal strong associations between brain region–specific loss of gray matter, reduced spine density and functional hypoactivity in schizophrenia.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Postmortem studies support the view that spine density changes directly contribute to gray matter loss in schizophrenia.

    “Several postmortem studies have examined spine density changes in brain regions showing the greatest indices of gray matter loss in schizophrenia and these results support the view that spine density changes directly contribute to gray matter loss in the disease3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Selemon, L.D. & Goldman-Rakic, P.S. The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol. Psychiatry 45, 17–25 (1999). source

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    Premisecitation

    In post-mortem ASD brain tissue, spine density is increased on apical dendrites of pyramidal neurons in cortical layer 2 of frontal, temporal, and parietal lobes, and in layer 5 only in the temporal lobe.

    “This recent evidence from Golgi-impregnated post-mortem ASD human brain tissue revealed an increase in spine density on apical dendrites of pyramidal neurons from cortical layer 2 in frontal, temporal and parietal lobes and layer 5 only in the temporal lobe4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Hutsler, J.J. & Zhang, H. Increased dendritic spine densities on cortical projection neurons in autism spectrum disorders. Brain Res. 1309, 83–94 (2010). source

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    Premisecitation

    The dorsolateral prefrontal cortex shows severe dysfunction in schizophrenia, with reduced activity during cognitive tasks.

    “The dorsolateral prefrontal cortex (DLPFC) shows severe dysfunction in schizophrenia, as affected individuals show reduced activity of this region during cognitive tasks13.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Tan, H.Y., Callicott, J.H. & Weinberger, D.R. Dysfunctional and compensatory prefrontal cortical systems, genes and the pathogenesis of schizophrenia. Cereb. Cortex 17, i171–i181 (2007). source

      Not checked in the free run.

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    Interpretationreasoning

    Because symptoms of ASD, schizophrenia, and Alzheimer's disease appear at different life stages, dysregulation of synaptic structure and function may coincide with distinct cognitive and behavioral deficits depending on when it occurs.

    “Notably, the symptoms of each of these disorders manifest at distinct stages of life, suggesting that dysregulation of synaptic structure and function can coincide with unique deficits in cognition and behavior depending on when the disruptions occur across the lifespan (Fig. 1).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Symptoms of ASD, schizophrenia, and Alzheimer's disease manifest at distinct stages of life.

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    Premisecitation

    Synapse loss occurs in mild cognitive impairment and is greater in Alzheimer's disease, indicating that it begins early and worsens with disease progression.

    “Detailed analysis of postmortem tissue has revealed synapse loss in mild cognitive impairment (MCI), but an even greater loss in Alzheimer’s disease, indicating that synapse loss occurs early in the progression of Alzheimer’s disease and worsens as the disease advances21.”
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    • cites [21] Arendt, T. Synaptic degeneration in Alzheimer's disease. Acta Neuropathol. 118, 167–179 (2009). source

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    Premisecitation

    Gray matter loss is a defining neuropathological feature of schizophrenia and is accelerated during periadolescence.

    “One of the defining neuropathological features of schizophrenia is gray matter loss, which is accelerated during periadolescence12.”
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    • cites [12] Gogtay, N. Cortical brain development in schizophrenia: insights from neuroimaging studies in childhood-onset schizophrenia. Schizophr. Bull. 34, 30–36 (2008). source

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    Premisecitation

    Spine enlargement is associated with long-term potentiation, while long-term depression is associated with spine shrinkage.

    “for example, spine enlargement parallels long-term potentiation, whereas long-term depression is associated with spine shrinkage1.”
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    • cites [1] Kasai, H., Fukuda, M., Watanabe, S., Hayashi-Takagi, A. & Noguchi, J. Structural dynamics of dendritic spines in memory and cognition. Trends Neurosci. 33, 121–129 (2010). source

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    Premisecitation

    The fragile X brain shows elevated spine density, thought to result from pruning deficits, with elongated and tortuous spine morphologies.

    “Similar to ‘pure’ autism, the fragile X brain is characterized by elevated spine density, which is thought to result from pruning deficits, with elongated, tortuous spine morphologies11, indicative of altered function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Irwin, S.A. et al. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am. J. Med. Genet. 98, 161–167 (2001). source

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    Premisecitation

    Schizophrenia is associated with reduced hippocampal volume and reduced spine density on subicular and CA3 dendrites.

    “Several studies have shown reductions in hippocampal volume and reduced spine density on subicular and CA3 dendrites in schizophrenia16,17.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Steen, R.G., Mull, C., McClure, R., Hamer, R.M. & Lieberman, J.A. Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies. Br. J. Psychiatry 188, 510–518 (2006). source

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    • cites [17] Kolomeets, N.S., Orlovskaya, D.D., Rachmanova, V.I. & Uranova, N.A. Ultrastructural alterations in hippocampal mossy fiber synapses in schizophrenia: a postmortem morphometric study. Synapse 57, 47–55 (2005). source

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    Interpretationreasoning

    NLGN3, NRXN1, Epac2, and the Shank proteins form a synaptic regulatory pathway whose disruption could produce ASD-like synapse pathology.

    “Thus, NLGN3, NRXN1, Epac2 and the Shank proteins constitute members of a synaptic regulatory pathway, disruption of which could confer ASD-like synapse pathology.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Rare mutations and copy number variants in genes encoding synaptic proteins have been identified in autistic individuals, supporting a role for synaptic dysfunction in ASD etiology.

    “Notably, multiple reports have identified rare mutations and CNVs in genes encoding synaptic proteins in autistic individuals, supporting the hypothesis that synaptic dysfunction may be important in the etiology of ASDs8.”
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    • cites [8] Toro, R. et al. Key role for gene dosage and synaptic homeostasis in autism spectrum disorders. Trends Genet. 26, 363–372 (2010). source

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    Premisecitation

    ZDHHC8 palmitoylates PSD-95; its loss reduces spine density and simplifies dendrites, and replacement rescues spine and dendrite deficiency in Df(16)A+/− neurons.

    “ZDHHC8 is a palmitoyl transferase that palmitoylates the postsynaptic density scaffolding molecule PSD-95; ZDHHC8 loss results in reduced spine density and simpler dendrites and its replacement into Df(16)A+/− neurons rescued spine and dendrite deficiency51.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Mukai, J. et al. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat. Neurosci. 11, 1302–1310 (2008). source

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    Interpretationreasoning

    In schizophrenia, it is likely that spine formation and stability are reduced or spine pruning is accelerated.

    “Although postmortem studies cannot identify the root cause of spine loss, it is likely that spine formation and stability are reduced or spine pruning is accelerated in schizophrenia (Fig. 1).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Neuregulins are trophic factors that exist in membrane-bound and soluble forms, and ErbB receptors are postsynaptic receptor tyrosine kinases activated by neuregulin binding.

    “Neuregulins are trophic factors that exist in both membrane-bound and soluble form. ErbB receptors are postsynaptic receptor tyrosine kinases and are activated on neuregulin binding47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Mei, L. & Xiong, W.C. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat. Rev. Neurosci. 9, 437–452 (2008). source

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    Premisecitation

    PTEN deficiency results in dendritic hypertrophy and elevated spine density.

    “PTEN deficiency results in dendritic hypertrophy and elevated spine density41”
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    • cites [41] Kwon, C.H. et al. Pten regulates neuronal arborization and social interaction in mice. Neuron 50, 377–388 (2006). source

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    Premisecitation

    Mutations in TSC1, TSC2, or PTEN are frequently diagnosed with autism, and each of these proteins regulates synaptic structure.

    “Individuals with mutations of tuberous sclerosis proteins 1 and 2 (TSC1, TSC2) or the phosphatase and tensin homolog (PTEN) gene, which causes macroencephaly, are frequently diagnosed with autism38 and each of these proteins regulates synaptic structure39,40.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [38] Butler, M.G. et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J. Med. Genet. 42, 318–321 (2005). source

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    • cites [39] Tavazoie, S.F., Alvarez, V.A., Ridenour, D.A., Kwiatkowski, D.J. & Sabatini, B.L. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat. Neurosci. 8, 1727–1734 (2005). source

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    • cites [40] Fraser, M.M., Bayazitov, I.T., Zakharenko, S.S. & Baker, S.J. Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities. Neuroscience 151, 476–488 (2008). source

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    Interpretationreasoning

    Neuropathological evidence points toward synapse and dendritic spine loss in schizophrenia and Alzheimer's disease, whereas ASDs appear characterized by increased spine numbers.

    “In summary, neuropathological evidence points toward synapse and dendritic spine loss in schizophrenia and Alzheimer’s disease, whereas ASDs seem characterized by increased spine numbers.”
    Quote in the paperSubstantial claim

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    Premisecitation

    NLGN3 or NLGN4 increase excitatory synapse number in hippocampal neurons, and the NLGN3 Arg451Cys variant prevents this induction.

    “Data gleaned from cell biological studies have shown that NLGN3 or NLGN4 increase excitatory synapse number in hippocampal neurons and the NLGN3 Arg451Cys variant prevents this induction of synapse formation29”
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    • cites [29] Chih, B., Afridi, S.K., Clark, L. & Scheiffele, P. Disorder-associated mutations lead to functional inactivation of neuroligins. Hum. Mol. Genet. 13, 1471–1477 (2004). source

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    Premisecitation

    The initial link of DISC1 to schizophrenia was identified in a Scottish pedigree with a disruption of the DISC1 open reading frame.

    “The initial link of the disrupted in schizophrenia 1 (DISC1) gene to schizophrenia was identified in a Scottish pedigree with a disruption of the DISC1 open reading frame52.”
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    • cites [52] St. Clair, D. et al. Association within a family of a balanced autosomal translocation with major mental illness. Lancet 336, 13–16 (1990). source

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    Premisecitation

    De novo copy number variants and an inherited point mutation in SHANK2 have been identified in patients with ASD and mental retardation.

    “more recently, de novo CNVs and inherited point mutation have been identified in the SHANK2 gene in patients with ASD and mental retardation32.”
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    • cites [32] Berkel, S. et al. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat. Genet. 42, 489–491 (2010). source

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    Study design and conductreasoning

    Neuropathological studies are performed at advanced disease stages, reflect an endpoint, and cannot distinguish cause, consequence, compensation, or confound.

    “As these neuropathological studies are performed in an advanced stage of the disease, they reflect an endpoint of the disease process and do not distinguish between cause, consequence, compensation or confound.”
    Quote in the paperSubstantial claim

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    Premisecitation

    ErbB4 overexpression increases spine density, area, and excitatory synaptic transmission.

    “ErbB4 overexpression increases spine density, area and excitatory synaptic transmission49.”
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    • cites [49] Li, B., Woo, R.S., Mei, L. & Malinow, R. The neuregulin-1 receptor erbB4 controls glutamatergic synapse maturation and plasticity. Neuron 54, 583–597 (2007). source

      Not checked in the free run.

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    Premisecitation

    Epac2 missense mutations increase dendritic spine number and area.

    “Epac2 missense mutations increase dendritic spine number (Epac2-T809S) and area (Epac2-V646F)36.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Woolfrey, K.M. et al. Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat. Neurosci. 12, 1275–1284 (2009). source

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    Premisecitation

    Shank3 may complex with and signal downstream of NLGNs.

    “and Shank3 may complex with and signal downstream of NLGNs37.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] Bourgeron, T. A synaptic trek to autism. Curr. Opin. Neurobiol. 19, 231–234 (2009). source

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    Premisecitation

    In schizophrenia, spine loss occurs in layer 3 of the dorsolateral prefrontal cortex but not in layers 5 and 6.

    “Notably, in schizophrenia, loss of spines occurs in layer 3 of the DLPFC5, but not in layers 5 and 6 (ref. 23).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Glantz, L.A. & Lewis, D.A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000). source

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    • cites [23] Kolluri, N., Sun, Z., Sampson, A.R. & Lewis, D.A. Lamina-specific reductions in dendritic spine density in the prefrontal cortex of subjects with schizophrenia. Am. J. Psychiatry 162, 1200–1202 (2005). source

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    Premisecitation

    Fragile X syndrome results from transcriptional silencing of FMR1, which causes upregulated global dendritic translation rates that may contribute to elevated spine density.

    “Fragile X syndrome results from transcriptional silencing of the FMR1 gene, which in turn causes an upregulation in global dendritic translation rates that may contribute to the elevated spine density observed in the brains of affected individuals42.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Bagni, C. & Greenough, W.T. From mRNP trafficking to spine dysmorphogenesis: the roots of fragile X syndrome. Nat. Rev. Neurosci. 6, 376–387 (2005). source

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

    Premisecitation

    The 22q11.2 microdeletion syndrome is the most common copy number variant associated with schizophrenia, accounting for 1-2% of cases.

    “The 22q11.2 microdeletion syndrome is the most common CNV associated with schizophrenia, accounting for 1–2% of cases50.”
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    • cites [50] Stark, K.L. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat. Genet. 40, 751–760 (2008). source

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    Premisecitation

    NLGN3 complexes with Epac2 and enhances its signaling activity.

    “Notably, NLGN3 also complexes with Epac2 and enhances its signaling activity36”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Woolfrey, K.M. et al. Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nat. Neurosci. 12, 1275–1284 (2009). source

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    Study design and conductnone given

    Postmortem human tissue studies have caveats including postmortem interval, symptomatic heterogeneity, and patient medical history.

    “Several caveats must accompany studies of postmortem human tissue, such as postmortem interval, symptomatic heterogeneity and patient medical history.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Dgcr8 is involved in miRNA processing, and its loss results in smaller spines and simpler dendrites.

    “Dgcr8 is involved in miRNA processing and its loss results in smaller spines and simpler dendrites50.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Stark, K.L. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat. Genet. 40, 751–760 (2008). source

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    Interpretationcitation

    Synapse loss in Alzheimer's disease often exceeds what neuronal death would predict, indicating that synaptic dysgenesis is a prominent pathology rather than a byproduct and contributes to cognitive decline.

    “Furthermore, synapse loss often appears greater than what would be expected from neuronal death, underscoring synaptic dysgenesis as a prominent pathology of Alzheimer’s disease, rather than a byproduct, and a driving factor in cognitive decline19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Walsh, D.M. & Selkoe, D.J. Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron 44, 181–193 (2004). source

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    Premisecitation

    NRG1 and erbB4 regulate spine structure and function, and long-term NRG1 treatment increases pyramidal neuronal spine density and the proportion of mature spine phenotypes.

    “NRG1 and erbB4 regulate spine structure and function; long-term NRG1 treatment increases pyramidal neuronal spine density and the preponderance of spines with mature phenotypes48.”
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    • cites [48] Barros, C.S. et al. Impaired maturation of dendritic spines without disorganization of cortical cell layers in mice lacking NRG1/ErbB signaling in the central nervous system. Proc. Natl. Acad. Sci. USA 106, 4507–4512 (2009). source

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    Premisecitation

    Shank2 is implicated in activity-dependent spine remodeling.

    “whereas Shank2 has been implicated in activity-dependent spine remodeling34.”
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    • cites [34] Steiner, P. et al. Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity. Neuron 60, 788–802 (2008). source

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    Premisecitation

    Several missense mutations in KALRN have been identified in schizophrenia, occur in conserved regions, and are predicted to have functional consequences.

    “Recently, several missense mutations in the KALRN gene were identified in schizophrenia. These mutations occurred in evolutionary conserved gene regions and are predicted to have functional consequences57.”
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    • cites [57] Kushima, I. et al. Resequencing and association analysis of the KALRN and EPHB1 genes and their contribution to schizophrenia susceptibility. Schizophr. Bull. published online, doi:10.1093/schbul/sbq118 (1 November 2010). source

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    Premisecitation

    Expression of DISC1-interacting proteins is reduced in individuals carrying high-risk DISC1 SNPs, suggesting that DISC1 function might be affected in schizophrenia.

    “the expression of DISC1-interacting proteins was reduced in individuals carrying high-risk DISC1 SNPs55, suggesting that DISC1 function might be affected in schizophrenia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Lipska, B.K. et al. Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs. Hum. Mol. Genet. 15, 1245–1258 (2006). source

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    Interpretationnone given

    Genetic data suggest Aβ is vital for Alzheimer's disease pathogenesis, and molecular studies indicate Aβ acts on synapses to mediate toxic effects.

    “An abundance of genetic data suggests that Aβ is vital for Alzheimer’s disease pathogenesis and molecular studies indicate that Aβ acts on synapses to mediate its toxic effects.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The APOE ε4 allele is associated with greater risk of Alzheimer's disease, whereas APOE ε2 is considered neuroprotective.

    “Specifically, the ε4 (APOE ε4) allele is associated with greater risk of developing Alzheimer’s disease, whereas APOE ε2 is considered to be neuroprotective.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Drebrin is reduced in the brains of individuals with Alzheimer's disease and in transgenic animal models.

    “Drebrin, a postsynaptic protein that binds and stabilizes actin in spines, is reduced in the brains of individuals with Alzheimer’s disease and in transgenic animal models of the disease20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Knobloch, M. & Mansuy, I.M. Dendritic spine loss and synaptic alterations in Alzheimer's disease. Mol. Neurobiol. 37, 73–82 (2008). source

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    Premisecitation

    PICALM, a GWAS susceptibility gene, is associated with inducing dendritic dystrophy and disrupting vesicle transport when underexpressed in embryonic hippocampal neurons.

    “Notably, PICALM, another susceptibility gene identified by GWAS, has been associated with inducing dendritic dystrophy and disrupting vesicle transport when underexpressed in embryonic hippocampal neurons65.”
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    • cites [65] Sleegers, K. et al. The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects. Trends Genet. 26, 84–93 (2010). source

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    Premisecitation

    Aβ oligomers target spines, induce spine dysgenesis, and reduce spine density.

    “Furthermore, Aβ oligomers have been clearly shown to target spines, induce spine dysgenesis, and reduce spine density63,64.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [63] Lacor, P.N. et al. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J. Neurosci. 27, 796–807 (2007). source

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    • cites [64] Shankar, G.M. et al. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor–dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007). source

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    Premisecitation

    Cofilin and drebrin are actin-binding proteins with opposite effects on actin dynamics, and both are affected in Alzheimer's disease.

    “Cofilin and drebrin are actin-binding proteins that exert opposite effects on actin dynamics, but both are affected in Alzheimer’s disease.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Active cofilin causes actin destabilization, and much evidence supports a role for cofilin in neurodegeneration, including Alzheimer's disease.

    “Active cofilin causes actin destabilization and much evidence supports a role for cofilin in neurodegeneration, including Alzheimer’s disease20.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Knobloch, M. & Mansuy, I.M. Dendritic spine loss and synaptic alterations in Alzheimer's disease. Mol. Neurobiol. 37, 73–82 (2008). source

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    Premisecitation

    Familial Alzheimer's disease has autosomal dominant inheritance and early onset and is associated with mutations in APP, PSEN1, and PSEN2, which are critical for Aβ production.

    “Familial Alzheimer’s disease, which has an autosomal dominant form of inheritance and early onset, has been associated with mutations in APP, PSEN1 and PSEN2, three genes that are critical for beta amyloid (Aβ) production61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Bertram, L. & Tanzi, R.E. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat. Rev. Neurosci. 9, 768–778 (2008). source

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    Premisecitation

    A recent independent GWAS reaffirmed APOE as the primary Alzheimer's disease genetic risk factor and identified new late-onset Alzheimer's disease susceptibility genes.

    “A recent independent GWAS, in addition to reaffirming APOE as the primary Alzheimer’s disease genetic risk factor, identified new LOAD susceptibility genes65.”
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    • cites [65] Sleegers, K. et al. The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects. Trends Genet. 26, 84–93 (2010). source

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    Premisecitation

    Pharmacological inhibition of PAK in mice is sufficient to cause memory impairment, cofilin pathology, and drebrin loss.

    “Furthermore, pharmacological inhibition of PAK in mice was sufficient to cause memory impairment, cofilin pathology and drebrin loss.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    CLU has many similarities to ApoE, including the ability to bind Aβ.

    “One example is the gene encoding for clusterin (CLU), also known as ApoJ, which has many similarities to ApoE, including the ability to bind Aβ.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mutations in familial Alzheimer's disease increase Aβ production, and cellular studies provide compelling evidence that soluble Aβ oligomers disrupt synaptic signaling.

    “Mutations found in familial Alzheimer’s disease are well known to increase Aβ production and cellular studies provide compelling evidence that soluble Aβ oligomers disrupt synaptic signaling (reviewed in ref. 62).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Selkoe, D.J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192, 106–113 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Loss of scaffolding proteins in spines could alter glutamatergic receptor signaling, which is theorized to contribute to schizophrenia etiology.

    “A loss of scaffolding proteins in spines could alter glutamatergic receptor signaling, disruption of which is theorized to contribute to the etiology of schizophrenia60.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Coyle, J.T. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell. Mol. Neurobiol. 26, 365–384 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The major genetic risk factor for late-onset Alzheimer's disease affects dendrite and spine morphology, but the underlying mechanisms remain unknown.

    “It is fascinating that the major genetic risk factor for LOAD affects dendrite and spine morphology, but the underlying mechanisms remain unknown and require further investigation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    PAK is a critical regulator of actin assembly in spines and a downstream effector of Rac.

    “A critical regulator of actin assembly in spines is p21-activated kinase (PAK), a downstream effector molecule of Rac69,70.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [69] Zhao, L. et al. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat. Neurosci. 9, 234–242 (2006). source

      Not checked in the free run.

    • cites [70] Penzes, P., et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37, 263–274 (2003). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Calcineurin is a calcium-sensitive phosphatase involved in synaptic plasticity whose activation leads to synaptic weakening, and Alzheimer's disease-related pathology increases activation of GSK-3β.

    “Calcineurin (CaN or PP2B) is a calcium-sensitive phosphatase involved in synaptic plasticity whose activation leads to synaptic weakening and Alzheimer’s disease–related pathology has been shown to increase activation of GSK-3β, a downstream effector molecule of calcineurin74,75.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [74] Li, S. et al. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801 (2009). source

      Not checked in the free run.

    • cites [75] Tackenberg, C. & Brandt, R. Divergent pathways mediate spine alterations and cell death induced by amyloid-beta, wild-type tau, and R406W tau. J. Neurosci. 29, 14439–14450 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Kalrn knockout mice exhibit schizophrenia-related deficits in working memory, sociability, and prepulse inhibition.

    “Notably, Kalrn−/− mice show severe reductions in spine density and dendrite complexity in the frontal cortex, as well as schizophrenia-related impairments in working memory, sociability and prepulse inhibition92,93.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Cahill, M.E. et al. Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes. Proc. Natl. Acad. Sci. USA 106, 13058–13063 (2009). source

      Not checked in the free run.

    • cites [93] Xie, Z., Cahill, M.E. & Penzes, P. Kalirin loss results in cortical morphological alterations. Mol. Cell. Neurosci. 43, 81–89 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tg2576 mice express mutant human APP and have lower spine density in CA1 and dentate gyrus before amyloid plaques appear.

    “The widely used Tg2576 mouse model expresses mutant human APP and displays decreased spine density in the CA1 and dentate gyrus, well before the development of amyloid plaques, further evidence that soluble Aβ oligomers initiate at least some Alzheimer’s disease–related pathology68,95.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [68] Lanz, T.A., Carter, D.B. & Merchant, K.M. Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype. Neurobiol. Dis. 13, 246–253 (2003). source

      Not checked in the free run.

    • cites [95] Jacobsen, J.S. et al. Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer′s disease. Proc. Natl. Acad. Sci. USA 103, 5161–5166 (2006). source

      Not checked in the free run.

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

    Interpretationcitation

    Discrepancies between adult social approach tests, statistical analyses, and genetic background may explain the contradictory results between the two NLGN3-R451C mouse models.

    “As suggested by the authors81, discrepancies between experimental designs of the adult social approach tests, statistical analyses and genetic background of the two mouse models may be the source of these contradictory results.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Chadman, K.K. et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res. 1, 147–158 (2008). source

      Not checked in the free run.

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

    Premisenone given

    Very little is known about spine morphology in ASD animal models.

    “Surprisingly, however, very little is known about spine morphology in ASD animal models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A hemizygous chromosomal deficiency mouse model of human 22q11.2 microdeletion displays schizophrenia-related behaviors: impaired working memory, hyperactivity, deficient sensory-motor gating, and impaired fear learning.

    “Moreover, mice with a hemizygous chromosomal deficiency modeling the human 22q11.2 microdeletion syndrome have schizophrenia-related behavioral phenotypes, including impaired working memory, hyperactivity, deficient sensory-motor gating and impaired fear learning50.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Stark, K.L. et al. Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model. Nat. Genet. 40, 751–760 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ reduces surface expression of NMDARs and AMPARs, and synaptotoxic effects of Aβ can be prevented by NMDAR antagonists.

    “studies showing that Aβ reduces surface expression of NMDARs and AMPARs77,78 and others demonstrate synaptotoxic effects of Aβ can be prevented by NMDAR antagonists64.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [77] Hsieh, H. et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006). source

      Not checked in the free run.

    • cites [78] Snyder, E.M. et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci. 8, 1051–1058 (2005). source

      Not checked in the free run.

    • cites [64] Shankar, G.M. et al. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor–dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In in vitro and in vivo models of Alzheimer's disease, Aβ oligomers produce aberrant long-term potentiation expression and impair memory.

    “Moreover, in vitro and in vivo models of Alzheimer’s disease, Aβ oligomers produce aberrant long-term potentiation expression and impair memory62.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Selkoe, D.J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192, 106–113 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Aberrant NMDAR activation can induce calcium signaling perturbations, and most signaling molecules discussed are downstream of NMDARs.

    “Aberrant NMDAR activation can induce calcium signaling perturbations and, indeed, most of the signaling molecules discussed above are known to be downstream of NMDARs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Spine loss and behavioral dysfunction both appeared during adolescence in Kalrn knockout mice.

    “Both spine loss and behavioral dysfunction emerged during adolescence92.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Cahill, M.E. et al. Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes. Proc. Natl. Acad. Sci. USA 106, 13058–13063 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Df(16)A+/− mouse model of 22q11.2 microdeletion syndrome has reduced hippocampal spine density and spine size.

    “Mice modeling the 22q11.2 microdeletion syndrome (Df(16)A+/−) show reduced hippocampal spine density and sizes51.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Mukai, J. et al. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat. Neurosci. 11, 1302–1310 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLGN3-R451C transgenic mice display impaired social interaction, enhanced Morris water maze performance, and enhanced inhibitory synaptic strength.

    “NLGN3-R451C transgenic mice display impaired social interaction behavior, but show enhanced performance in the Morris water maze, as well as enhanced inhibitory synaptic strength80.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Tabuchi, K. et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ZDHHC8-deficient mice have simplified dendritic trees and lower spine density.

    “Mice deficient in individual genes in this region (ZDHHC8 and DGCR8) show simplified dendritic trees and reduced spine density51 or smaller spines50, respectively.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Mukai, J. et al. Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion. Nat. Neurosci. 11, 1302–1310 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Pharmacological and genetic manipulations have rescued both structural and behavioral phenotypes in PTEN, FMR1, and MECP2 knockout mice.

    “Notably, pharmacological and genetic manipulations have successfully rescued both structural and behavioral phenotypes in PTEN86, FMR1 (ref. 87) and MECP2 (ref. 88) knockout mice.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [86] Zhou, J. et al. Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice. J. Neurosci. 29, 1773–1783 (2009). source

      Not checked in the free run.

    • cites ref. 87

      Not checked in the free run.

    • cites ref. 88

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NLGN4−/− knockout mice exhibit social interaction deficits and reduced ultrasonic vocalizations in response to a novel female, but dendritic spine morphology has not been analyzed.

    “NLGN4−/− knockout mice exhibit social interaction deficits and reduced ultrasonic vocalizations in response to a novel female82, but, again, dendritic spine morphology has not been analyzed in this model.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Jamain, S. et al. Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc. Natl. Acad. Sci. USA 105, 1710–1715 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Independently generated NLGN3-R451C transgenic mice have delayed developmental phenotypes, decreased ultrasonic vocalizations, slower righting reflexes, but no changes in social interaction or spatial learning.

    “In contrast, independently generated NLGN3-R451C transgenic mice were observed to have delayed developmental phenotypes, such as decreased ultrasonic vocalizations and slower righting reflexes, but no changes were seen in social interaction or spatial learning as measured by Morris water maze81.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Chadman, K.K. et al. Minimal aberrant behavioral phenotypes of neuroligin-3 R451C knockin mice. Autism Res. 1, 147–158 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutant mice for NRG1 and ERBB4 display multiple schizophrenia-relevant behaviors; locomotor hyperactivity is consistently present and often responds to acute clozapine.

    “NRG1 and ERBB4 mutant mice show several schizophrenia-relevant behavioral phenotypes, of which locomotor hyperactivity has been a consistent phenotype and can often be rescued through an acute dosage of the antipsychotic clozapine47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Mei, L. & Xiong, W.C. Neuregulin 1 in neural development, synaptic plasticity and schizophrenia. Nat. Rev. Neurosci. 9, 437–452 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Therapies aimed at trophic and morphogenic signaling may be more effective, altering connectivity with fewer side effects.

    “Indeed, many of the proteins in these pathways are enzymes that could be targeted with designer small molecules and drugs that target trophic and morphogenic signaling pathways may prove to be more effective, as they could alter cellular connectivity and induce fewer side effects.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Within these heterogeneous disorders, individuals with worse cognitive deficits may have more pronounced spine phenotypes.

    “Given the heterogeneity of these complex disorders, some individuals may exhibit more marked spine phenotypes, particularly those with more severe cognitive deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Near amyloid deposits, dendrites reportedly undergo shaft atrophy, neurite breakage, and greater spine density loss.

    “Specifically, dendrites near amyloid deposits are reported to experience shaft atrophy, neurite breakage and greater reductions in spine density97.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Tsai, J., Grutzendler, J., Duff, K. & Gan, W.B. Fibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches. Nat. Neurosci. 7, 1181–1183 (2004). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Many proteins in these pathways are enzymes amenable to targeting by designer small molecules.

    “Indeed, many of the proteins in these pathways are enzymes that could be targeted with designer small molecules and drugs that target trophic and morphogenic signaling pathways may prove to be more effective, as they could alter cellular connectivity and induce fewer side effects.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Evidence that spine loss is an initial insult comes from Tg2576 mice and from genetic studies linking synaptic proteins to etiology.

    “Support for the idea that spine loss is an initial insult comes from model mice, such as Tg2576, and from genetic studies that directly implicate synaptic proteins in etiology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    APP/PS1 mutant mice have neurons with fewer large spines and dendritic abnormalities.

    “Mice expressing mutations in both APP and PS1 yield neurons with diminished frequency of large spines and dendritic abnormalities96.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [96] Knafo, S. et al. Widespread changes in dendritic spines in a model of Alzheimer's disease. Cereb. Cortex 19, 586–592 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Disease-related spine changes affect synaptic function and circuit-level connectivity.

    “Spine changes in disease have implications for both functional changes at the synapse and circuit-level connectivity, in the form of altered connectivity or changes in connection strength.”
    Quote in the paperSubstantial claim
73 of 73

  • The paper relies on this without support.

    Most glutamatergic excitatory synapses in the mammalian forebrain occur on dendritic spines.

    “In the mammalian forebrain, most glutamatergic excitatory synapses occur on small protrusions along dendrites called dendritic spines.”

  • The paper relies on this without support.

    Changes in dendritic spine number and morphology accompany synapse formation, maintenance, and elimination during development and adulthood.

    “During development and in adulthood, changes in dendritic spine number and morphology accompany synapse formation, maintenance and elimination, allowing the establishment and remodeling of connectivity within neuronal circuits.”

  • The paper relies on this without support.

    Disease-specific disruptions in dendritic spine shape, size, or number accompany many brain disorders.

    “Notably, disease-specific disruptions in dendritic spine shape, size or number accompany a large number of brain disorders, suggesting that dendritic spines may serve as a common substrate for many neuropsychiatric disorders, particularly those that involve deficits in information processing.”

  • The paper relies on this without support.

    ASD, schizophrenia, and Alzheimer's disease are characterized by marked disruptions in information processing and cognition.

    “ASD, schizophrenia and Alzheimer’s disease are neurological disorders that are characterized by marked disruptions in information processing and cognition”

  • The paper relies on this without support.

    Symptoms of ASD, schizophrenia, and Alzheimer's disease manifest at distinct stages of life.

    “Notably, the symptoms of each of these disorders manifest at distinct stages of life”

  • The paper relies on this without support.

    Over 240 gene variants have been associated with schizophrenia.

    “Over 240 gene variants have been associated with schizophrenia.”

  • The paper relies on this without support.

    Alzheimer's disease can result from highly penetrant genetic mutations that faithfully give rise to the pathological hallmarks of the disease.

    “Alzheimer’s disease can result from highly penetrant genetic mutations that faithfully give rise to the pathological hallmarks of the disease.”

  • The paper relies on this without support.

    ASD is associated with local hyperconnectivity and long-range hypoconnectivity, whereas schizophrenia is associated with reduced short- and long-range connectivity.

    “As ASD seems to be associated with local hyperconnectivity and long-range hypoconnectivity, whereas schizophrenia is associated with reduced short- and long-range connectivity, it would be of interest to determine the effects of disease genes and mutations on the growth and maintenance of dendrites and axons to address changes in circuit organization in these disease states.”
8 of 8

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?

  • Precocious brain development was previously associated with specific forms of NDD, including ASD.

    “Precocious brain development was previously associated with specific forms of NDD, including ASD,11,61 and in vitro PSC models have recently suggested altered timing of neuronal differentiation in some forms of ASD.62”

    From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [61]

    The Genetics and molecular mechanisms section links autism with PTEN mutations associated with macroencephaly and reports dendritic hypertrophy with PTEN deficiency. It does not establish that brain development occurs precociously or identify an accelerated developmental timetable in ASD. Page numbers are unavailable in our copy. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • Disruption in dendritic morphogenesis, synaptogenesis or activity-dependent remodelling produces network-wide deficits in neuronal connectivity.

    “A disruption in any of these processes produces network-wide deficits in neuronal connectivity”

    From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [17]

    The Abstract (page unavailable) says spine changes help establish and remodel circuit connectivity and may markedly affect connectivity patterns. The Conclusions and future directions (page unavailable) links disease-related spine changes to altered circuit-level connectivity. Neither passage establishes that disruption of any one of the three named processes necessarily produces network-wide deficits; the claim makes the effect more categorical and extensive than the paper does. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Changes in morphological complexity, dendritic spine number, shape and plasticity are associated with several neuropsychiatric and neurological disorders, including schizophrenia, autism spectrum disorder, intellectual disability and epilepsy.

    “changes in morphological complexity, dendritic spine number, shape and plasticity are associated with several neuropsychiatric and neurological disorders, including SCZ, ASD, ID and epilepsy.16, 17, 18, 19”

    From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [17]

    The Abstract and ‘Neuropathological studies of spine morphology’ section associate changes in spine number and morphology with schizophrenia and ASD, and the latter also notes spine alterations in disorders historically termed mental retardation. The ‘Conclusions and future directions’ section mentions epilepsy as a comorbidity of ASD, but does not establish the claimed association between epilepsy itself and changes in dendritic spines. Page numbers are unavailable in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • This interpretation is supported by a large number of researchers who study dendritic spine alterations both in humans and animal models.

    “This interpretation is also supported by a large number of researchers who study dendritic spine alterations both in humans and animal models (see Penzes et al., 2011; Spires-Jones and Knafo, 2012 for recent reviews).”

    From The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease (2013) · cites this paper as Penzes et al., 2011

  • These disorders are synaptopathies in which dysgenesis of dendritic spines is a recurrent anatomical feature.

    “These disorders are synaptopathies (Ehninger and Silva, 2009) in which dysgenesis of dendritic spines is a recurrent anatomical feature (Penzes et al., 2011).”

    From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Penzes et al., 2011

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Authors
Penzes, P., Cahill, M. E., Jones, K. A., VanLeeuwen, J.-E., & Woolfrey, K. M.
Affiliations
Northwestern University (US)
Corresponding author
Penzes, Peter
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2011-02-23
Volume
14
Issue
3
Pages
285-293
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/nn.2741
PMC
PMC3530413
OpenAlex
W2040268226
Cited by
1,523
References
102
Citations by year
2026: 67 · 2025: 74 · 2024: 94 · 2023: 90 · 2022: 105 · 2021: 123 · 2020: 120 · 2019: 114 · 2018: 97 · 2017: 120 · 2016: 110 · 2015: 104 · 2014: 105 · 2013: 83 · 2012: 85
FWCI
9.27
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Neuroscience (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (1f31mh087043-01a1)
  • National Institute on Aging (F31AG031621)
  • National Institute of Mental Health (MH071533, 1F31MH087043, MH 071316, R01MH071533, R56MH071316, F31 MH087043, F31MH085362, R01MH071316)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
dendritic spines, synaptic pathology, autism spectrum disorder, schizophrenia, Alzheimer's disease, neuropsychiatric disorders, neurodegenerative diseases, pathogenesis, endophenotypes, therapeutic target, animal models, reverse translation
MeSH terms
Alzheimer Disease, Animals, Humans, Nerve Tissue Proteins, Nervous System Diseases, Schizophrenia, Dendritic Spines

About these checks

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 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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