CoChat
Sign Up
Cited by 666Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchNeuroscience and Neuropharmacology Research

Activity-dependent neuronal signalling and autism spectrum disorder

Open access
Ebert, Daniel H., Greenberg, Michael E.·2013·Nature
DOI 10.1038/nature11860PMC PMC3576027
Open this paper in CoChat — free account

Abstract

Neuronal activity induces the post-translational modification of synaptic molecules, promotes localized protein synthesis within dendrites and activates gene transcription, thereby regulating synaptic function and allowing neuronal circuits to respond dynamically to experience. Evidence indicates that many of the genes that are mutated in autism spectrum disorder are crucial components of the activity-dependent signalling networks that regulate synapse development and plasticity. Dysregulation of activity-dependent signalling pathways in neurons may, therefore, have a key role in the aetiology of autism spectrum disorder.

Integrity signals

Registry

Crossref · 10.1038/nature11860

Cites

100 of 100 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 225 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    Many genes mutated in ASD are essential components of activity-dependent signalling networks that control synapse development and plasticity.

    “Evidence indicates that many of the genes that are mutated in autism spectrum disorders are crucial components of the activity-dependent signalling networks that regulate synapse development and plasticity.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Some ASD-associated mutations are limited to a specific gene and cause syndromic neurodevelopmental disorders with highly penetrant autism features, including Fragile X syndrome, tuberous sclerosis complex, Angelman syndrome, Timothy syndrome and Rett syndrome.

    “In some cases, the mutations are limited to a specific gene and result in syndromic neurodevelopmental disorders with highly penetrant features of autism. These include Fragile X syndrome, tuberous sclerosis complex, Angelman syndrome, Timothy syndrome and Rett syndrome2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Zoghbi, H. Y. & Bear, M. F. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb. Perspect. Biol. 4, a009886 (2012). source

      Not checked in the free run.

  • Interpretationreasoning

    Impairment of multiple, different molecular pathways that are not mutually exclusive probably contributes to the development of various subsets or aspects of ASD.

    “Indeed, impairment of multiple, different molecular pathways that are not mutually exclusive, probably contributes to the development of various subsets, or aspects, of ASD.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Rare genetic variations play a significant part in the aetiology of ASD.

    “Rare genetic variations play a significant part in the aetiology of ASD.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] State, M. W. & Levitt, P. The conundrums of understanding genetic risks for autism spectrum disorders. Nature Neurosci. 14, 1499–1506 (2011). source

      Not checked in the free run.

    • cites [32] Sanders, S. J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70, 863–885 (2011). source

      Not checked in the free run.

  • Interpretationreasoning

    Many mutations associated with ASD lead to alterations in excitatory or inhibitory neurotransmission that disrupt activity-dependent signalling and activity-dependent synapse development, maturation and refinement.

    “Many of the mutations associated with ASD lead to alterations in excitatory or inhibitory neurotransmission that disrupt activity-dependent signalling and disrupt activity-dependent synapse development, maturation and refinement.”
    Quote in the paperSubstantial claim
  • May combine two claims. 82
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Premisecitation

    ASD is polygenic, with recent studies of de novo exonic mutations suggesting involvement of as many as 400 to 1,000 genetic loci.

    “ASD is polygenic in aetiology; recent studies of de novo exonic mutations suggest the involvement of as many as 400 to 1,000 genetic loci in ASD9.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] O'Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genet. 43, 585–589 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Synaptic stimulation induces specific changes in mRNA translation near synapses and sends signals to the nucleus that induce gene transcription programs controlling synaptic maturation and function.

    “Synaptic stimulation both induces specific changes in messenger RNA translation near synapses and sends signals to the nucleus to induce gene transcription programs that control synaptic maturation and function.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Greer, P. L. & Greenberg, M. E. From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59, 846–860 (2008). source

      Not checked in the free run.

    • cites [15] Cohen, S. & Greenberg, M. E. Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Annu. Rev. Cell Dev. Biol. 24, 183–209 (2008). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Many genes implicated in ASD could function in convergent molecular pathways, allowing formulation of specific mechanistic hypotheses that could explain significant portions of ASD.

    “However, as already suggested, many of the genes implicated in ASD could function in convergent molecular pathways, allowing for the formulation of specific mechanistic hypotheses that could explain significant portions of ASD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Most features of ASD appear in the first few years of life, a period when sensory experience modifies excitatory synapse maturation and elimination and promotes inhibitory synapse development.

    “Most of these features of ASD manifest in the first few years of life, at the time of brain development when sensory experience is modifying excitatory synapse maturation and elimination, and promoting the development of inhibitory synapses3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Flavell, S. W. & Greenberg, M. E. Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563–590 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuronal activity-dependent pathways are crucial for learning and memory and adaptive behavioural responses.

    “These neuronal activity-dependent pathways are crucial to learning and memory and for adaptive behavioural responses11–13.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001). source

      Not checked in the free run.

    • cites [12] Greer, P. L. & Greenberg, M. E. From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59, 846–860 (2008). source

      Not checked in the free run.

    • cites [13] Kelleher, R. J. III & Bear, M. F. The autistic neuron: troubled translation? Cell 135, 401–406 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuronal activity modifies synaptic molecules post-translationally, promotes local dendritic protein synthesis, and activates gene transcription, thereby regulating synaptic function and enabling circuits to adapt to experience.

    “Neuronal activity induces the post-translational modification of synaptic molecules, promotes localized protein synthesis within dendrites and activates gene transcription, thereby regulating synaptic function and allowing neuronal circuits to respond dynamically to experience.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] Kandel, E. R. The molecular biology of memory storage: a dialogue between genes and synapses. Science 294, 1030–1038 (2001). source

      Not checked in the free run.

    • cites [12] Greer, P. L. & Greenberg, M. E. From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59, 846–860 (2008). source

      Not checked in the free run.

    • cites [13] Kelleher, R. J. III & Bear, M. F. The autistic neuron: troubled translation? Cell 135, 401–406 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in RSK2, CBP, MECP2, and UBE3A cause Coffin-Lowry syndrome, Rubinstein-Taybi syndrome, Rett syndrome and Angelman syndrome, respectively.

    “Likewise, mutations in RSK2, CBP, the methyl-binding protein MECP2, and the ubiquitin ligase UBE3A are causes of Coffin–Lowry syndrome, Rubinstein–Taybi syndrome, Rett syndrome and Angelman syndrome, respectively3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Flavell, S. W. & Greenberg, M. E. Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu. Rev. Neurosci. 31, 563–590 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knock-in mice with the ASD-associated missense mutation Nlgn3(R704C) show decreased AMPA receptor-mediated synaptic transmission in the hippocampus, but no alteration in NMDA or GABA-receptor mediated neurotransmission.

    “Knock-in mice with another ASD-associated missense mutation, Nlgn3(R704C) displayed a decrease in AMPA receptor-mediated synaptic transmission in the hippocampus, but no alteration in NMDA or GABA (γ-aminobutyric acid)-receptor mediated neurotransmission39.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Etherton, M. R., Tabuchi, K., Sharma, M., Ko, J. & Sudhof, T. C. An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. 30, 2908–2919 (2011). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    It has been proposed that ASD may result, at least in part, from disruption of activity-dependent signalling networks that control gene transcription.

    “Only about 3% of the neuronal transcriptome is altered when the membrane is depolarized, but a higher percentage of the genes that are implicated in ASD have been shown to be regulated by neuronal activity, it has been proposed, therefore, that ASD may result, at least in part, from the disruption of the activity-dependent signalling networks that control gene transcription34,35.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Morrow, E. M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008). This paper provides evidence for the hypothesis that genetic mutations associated with ASD may disrupt activity-dependent gene expression programs. source

      Not checked in the free run.

    • cites [35] Chahrour, M. H. et al. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet. 8, e1002635 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Nrxn1 knock-out mice have defects in miniature EPSC frequency and evoked postsynaptic potentials, but no change in inhibitory neurotransmission in the hippocampus.

    “Nrxn1 knock-out mice have defects in miniature excitatory postsynaptic current (EPSC) frequency and evoked postsynaptic potentials, but show no change in inhibitory neurotransmission in the hippocampus40.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Etherton, M. R., Blaiss, C. A., Powell, C. M. & Sudhof, T. C. Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl Acad. Sci. USA 106, 17998–18003 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Several neuroligin mutations found in individuals with ASD have been modelled in mice, and these mice show alterations in excitatory or inhibitory neurotransmission.

    “Several of the neuroligin mutations found in individuals with ASD have been modelled in mice, and these mice have been shown to have alterations in excitatory or inhibitory neurotransmission.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [38] 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.

    • cites [39] Etherton, M. R., Tabuchi, K., Sharma, M., Ko, J. & Sudhof, T. C. An autism-associated point mutation in the neuroligin cytoplasmic tail selectively impairs AMPA receptor-mediated synaptic transmission in hippocampus. EMBO J. 30, 2908–2919 (2011). source

      Not checked in the free run.

    • cites [40] Etherton, M. R., Blaiss, C. A., Powell, C. M. & Sudhof, T. C. Mouse neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl Acad. Sci. USA 106, 17998–18003 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This suggests a role for neuroligins in experience-regulated learning and memory that may be altered by ASD-associated mutations in NLGN1.

    “This suggests a role for neuroligins in experience-regulated learning and memory which may be altered by ASD-associated mutations in NLGN1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The CGG expansion occurs in the 5′ untranslated region of FMRP mRNA, decreasing FMRP mRNA translation and reducing FMRP levels in neurons.

    “The CGG expansion occurs within the 5′ untranslated region of the FMRP mRNA, resulting in decreased translation of the FMRP mRNA and a decrease in the amount of FMRP expressed in neurons.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Bhakar, A. L., Dolen, G. & Bear, M. F. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Only about 3% of the neuronal transcriptome is altered by membrane depolarization, but a higher percentage of ASD-implicated genes are regulated by neuronal activity.

    “Only about 3% of the neuronal transcriptome is altered when the membrane is depolarized, but a higher percentage of the genes that are implicated in ASD have been shown to be regulated by neuronal activity, it has been proposed, therefore, that ASD may result, at least in part, from the disruption of the activity-dependent signalling networks that control gene transcription34,35.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Morrow, E. M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008). This paper provides evidence for the hypothesis that genetic mutations associated with ASD may disrupt activity-dependent gene expression programs. source

      Not checked in the free run.

    • cites [35] Chahrour, M. H. et al. Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. PLoS Genet. 8, e1002635 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of Nlgn1 in the amygdala of adult rats led to selective reduction of NMDA-receptor-mediated currents and impairments in LTP and storage of associative fear memory.

    “In another study42, knockdown of Nlgn1, delivered by a viral vector, in the amygdala of adult rats led to the selective reduction of NMDA-receptor-mediated currents, and impairments in LTP and in the storage of associative fear memory.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] Kim, J. et al. Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals. Proc. Natl Acad. Sci. USA 105, 9087–9092 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Particular neuroligin family members localize specifically to inhibitory or excitatory synapses, suggesting individual neuroligins may specify the formation or function of excitatory and inhibitory synapses.

    “Particular neuroligin family members are localized specifically to inhibitory or excitatory synapses, suggesting that individual neuroligins may play a part in specifying the formation or function of excitatory and inhibitory synapses.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Missler, M., Sudhof, T. C. & Biederer, T. Synaptic cell adhesion. Cold Spring Harb. Perspect. Biol. 4, a005694 (2012). source

      Not checked in the free run.

    • cites [37] Sudhof, T. C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fragile X syndrome is characterized by macroorchidism, connective-tissue disease, motor abnormalities, language deficits and impaired social interactions, and is the leading cause of inherited intellectual disability and ASD.

    “For example, Fragile X syndrome — characterized by macroorchidism, connective-tissue disease, motor abnormalities, language deficits and impaired social interactions — is the leading cause of inherited intellectual disability and ASD23.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Bhakar, A. L., Dolen, G. & Bear, M. F. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    These syndromic disorders are caused by single gene mutations and have readily diagnosable phenotypes, so their mechanistic understanding is more advanced than for most ASD.

    “These syndromic disorders are caused by single gene mutations and have phenotypes that have allowed the disorder to be readily diagnosed; thus, the mechanistic understanding of these syndromes is more advanced than for most ASD.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Because these proteins regulate synaptic responses to experience and are themselves modulated by neuronal activity, this supports the hypothesis that ASD may result from disruption of normal activity-dependent synapse development.

    “The fact that these proteins have key roles in regulating synaptic responses to experience, and are themselves modulated by neuronal activity supports the hypothesis that ASD may result from the disruption of the normal process of activity-dependent synapse development (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    FMRP modulates the rate of translational elongation of mRNAs encoding synaptic proteins, suggesting that reduced FMRP in Fragile X syndrome may dysregulate synaptic protein expression through impaired translational control.

    “FMRP has recently been reported to modulate the rate of translational elongation of mRNAs that encode synaptic proteins33, suggesting that the decrease in FMRP expression that occurs in Fragile X syndrome may result in the dysregulation of synaptic protein expression owing to an impairment in translational control23.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [33] Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011). source

      Not checked in the free run.

    • cites [23] Bhakar, A. L., Dolen, G. & Bear, M. F. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Because de novo mutations in coding regions occur with reasonable frequency and do not necessarily cause a deleterious phenotype, additional evidence is required before each mutation can unequivocally be said to contribute to ASD.

    “As de novo mutations within gene-coding regions occur with reasonable frequency and do not necessarily result in a deleterious phenotype, additional evidence is required before each of these mutations can unequivocally be said to contribute to ASD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neuroligins are postsynaptic membrane proteins that function as neurexin receptors and, together with neurexins, modulate synapse formation and function.

    “Neuroligins are postsynaptic membrane proteins that function as neurexin receptors and, working together with neurexins, modulate the formation and function of synapses16,37.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Missler, M., Sudhof, T. C. & Biederer, T. Synaptic cell adhesion. Cold Spring Harb. Perspect. Biol. 4, a005694 (2012). source

      Not checked in the free run.

    • cites [37] Sudhof, T. C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rare mutations in NLGN4, NLGN3, NRXN1, SHANK2, SHANK3, and CNTNAP2 have been identified in multiple individuals with ASD, suggesting these mutations contribute to the disorder.

    “More subtle, rare mutations in NLGN4, NLGN3, NRXN1, SHANK2, SHANK3, CNTNAP2 (ref. 5) have also been identified in multiple individuals with ASD, suggesting that these mutations also contribute these disorders.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] State, M. W. & Levitt, P. The conundrums of understanding genetic risks for autism spectrum disorders. Nature Neurosci. 14, 1499–1506 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These Nlgn3(R451C) knock-in mice also have enhanced inhibitory neurotransmission with no alterations in excitatory neurotransmission, resulting in a defect in excitatory-inhibitory balance.

    “These knock-in mice also have enhanced inhibitory neurotransmission with no alterations in excitatory neurotransmission, resulting in a defect in excitatory–inhibitory balance in the brain38.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] 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.

    Interpretationreasoning

    These studies indicate that particular ASD mutations in neurexins or neuroligins disrupt excitatory or inhibitory neurotransmission in specific ways and suggest that modelling ASD-associated mutations in mice will be important for elucidating how each mutation affects synaptic function and gives rise to ASD.

    “These studies indicate that particular ASD mutations in neurexins or neuroligins disrupt excitatory or inhibitory neurotransmission in the brain in specific ways and suggest that modelling ASD-associated mutations in mice will be important for elucidating how each mutation affects synaptic function and give rise to ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In cultured rodent neurons, overexpression of Nlgn1 increases the number of functional excitatory synapses, an effect dependent on NMDA receptors and activity-regulated CaMKII downstream of NMDA receptor activation.

    “In cultured neurons of rodents, overexpression of Nlgn1 increases the number of functional excitatory synapses, an effect that is dependent on NMDA receptors, as well as activity-regulated CaMKII that functions downstream of NMDA receptor activation to regulate of synaptic plasticity41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Chubykin, A. A. et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54, 919–931 (2007). This study reports the crucial role for neuroligins in activity-dependent synapse maturation and how this pathway is dysregulated by ASD-associated mutations in neuroligin. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    These findings suggest that neuroligins and neurexins modulate activity-dependent synaptic remodelling and long-term memory, and that ASD-associated mutations in neuroligins or neurexins may disrupt these processes.

    “Taken together, these findings suggest that neuroligins and neurexins modulate activity-dependent synaptic remodelling and long-term memory, and that ASD-associated mutations in neuroligins or neurexins may disrupt these processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Disruption of this activity-regulated enhancement impaired recruitment of AMPA receptors to the synaptic membrane, altering synaptic function.

    “Disruption of this activity-regulated enhancement impaired the recruitment of AMPA receptors to the synaptic membrane, thereby altering synaptic function44.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Thyagarajan, A. & Ting, A. Y. Imaging activity-dependent regulation of neurexin-neuroligin interactions using trans-synaptic enzymatic biotinylation. Cell 143, 456–469 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuronal activity induces insertion of neurexin and neuroligin into the synaptic membrane and suppresses their internalization, leading to an overall increase in trans-synaptic neurexin-neuroligin interaction.

    “Neuronal activity induced both the insertion of neurexin and neuroligin into the synaptic membrane and suppressed internalization of neurexin and neuroligin from the synaptic membrane, leading to an overall increase in the trans-synaptic neurexin–neuroligin interaction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Thyagarajan, A. & Ting, A. Y. Imaging activity-dependent regulation of neurexin-neuroligin interactions using trans-synaptic enzymatic biotinylation. Cell 143, 456–469 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Under normal conditions, FMRP suppresses mGluR-dependent protein synthesis and LTD.

    “suggesting that under normal conditions FMRP suppresses mGluR-dependent protein synthesis and LTD55.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746–7750 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fmr1 knockout mice show abnormally high protein synthesis and enhanced LTD in response to mGluR stimulation.

    “Fmr1 knockout mice exhibit abnormally high levels of protein synthesis and enhanced LTD in response to mGluR stimulation”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746–7750 (2002). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Shank family proteins modulate excitatory synapse function, and mutations in their genes might contribute to ASD.

    “Taken together, these studies have revealed how the Shank family of proteins modulate excitatory synapse function and begin to explain how mutations in the genes that encode them might lead to ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Shank proteins control synaptic function and plasticity, and their mutation might contribute to autism spectrum phenotypes.

    “Taken together, these studies begin to explain how Shank proteins control synaptic function and plasticity, and how their mutation might contribute to autism spectrum phenotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Neuronal activity controls alternative splicing of neurexin mRNA, which changes trans-synaptic signalling and presynaptic differentiation.

    “Neuronal activity also regulates alternative splicing of neurexin mRNA and, thus, alters trans-synaptic signalling and presynaptic differentiation45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Iijima, T. et al. SAM68 regulates neuronal activity-dependent alternative splicing of neurexin-1. Cell 147, 1601–1614 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Fmr1 knockout mice, dynamic translation of Arc mRNA in response to stimulation is impaired, and basal Arc protein level in dendrites is elevated.

    “In Fmr1 knockout mice, the dynamic translation of Arc mRNA in response to stimulation is impaired59,61, and the basal level of the Arc protein in dendrites is elevated61.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Park, S. et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59, 70–83 (2008). source

      Not checked in the free run.

    • cites [61] Niere, F., Wilkerson, J. R. & Huber, K. M. Evidence for a fragile X mental retardation protein-mediated translational switch in metabotropic glutamate receptor-triggered Arc translation and long-term depression. J. Neurosci. 32, 5924–5936 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The interaction between neurexins and neuroligins is regulated by neuronal activity, providing further evidence that mutations causing ASD might disrupt activity-dependent processes controlling synaptic function.

    “The interaction between neurexins and neuroligins is regulated by neuronal activity, providing further evidence that mutations that cause ASD might be disrupting activity-dependent processes that control synaptic function.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Thyagarajan, A. & Ting, A. Y. Imaging activity-dependent regulation of neurexin-neuroligin interactions using trans-synaptic enzymatic biotinylation. Cell 143, 456–469 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shank2 knockout mice show defects in NMDA-receptor-dependent excitatory neurotransmission and synaptic plasticity in the hippocampus.

    “Shank2 knockout mice models show defects in NMDA-receptor-dependent excitatory neurotransmission and synaptic plasticity in the hippocampus48,49.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [48] Schmeisser, M. J. et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012). source

      Not checked in the free run.

    • cites [49] Won, H. et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 (2012). References 47–49 demonstrate the role of Shanks in regulating excitatory neurotransmission. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shank3 knockout mice have social interaction deficits and repetitive behaviours such as excessive grooming that cause self-injury.

    “Shank3 knockout mice have deficits in social interactions and engage in repetitive behaviours, such as excessive grooming, that lead to self injury47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Peca, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shank proteins act as scaffolds in the postsynaptic density of excitatory synapses and control the organization of postsynaptic signalling complexes and synapse morphology and function.

    “Shank proteins function as scaffolds in the PSD of excitatory synapses that regulate the organization of postsynaptic signalling complexes, as well as the morphology and function of synapses17–19.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Naisbitt, S. et al. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23, 569–582 (1999). source

      Not checked in the free run.

    • cites [18] Sala, C. et al. Regulation of dendritic spine morphology and synaptic function by Shank and Homer. Neuron 31, 115–130 (2001). source

      Not checked in the free run.

    • cites [19] Sheng, M. & Kim, E. The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 3, a005678 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Translation of Arc mRNA is enhanced during and crucial for mGluR-dependent LTD.

    “Translation of Arc mRNA is enhanced during, and crucial for, mGluR-dependent LTD59,60.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Park, S. et al. Elongation factor 2 and fragile X mental retardation protein control the dynamic translation of Arc/Arg3.1 essential for mGluR-LTD. Neuron 59, 70–83 (2008). source

      Not checked in the free run.

    • cites [60] Waung, M. W., Pfeiffer, B. E., Nosyreva, E. D., Ronesi, J. A. & Huber, K. M. Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 59, 84–97 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Shank2 knockout mice show abnormalities in motor behaviour, vocalization, and socialization, which are phenotypes typical of ASD.

    “mice lacking Shank2 have abnormalities in motor behaviour, vocalization and socialization — phenotypes typically observed in ASD48,49.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Schmeisser, M. J. et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012). source

      Not checked in the free run.

    • cites [49] Won, H. et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 (2012). References 47–49 demonstrate the role of Shanks in regulating excitatory neurotransmission. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Abnormally high Arc expression in Fmr1 knockout mice may be responsible for enhanced mGluR-LTD and may explain why their LTD is independent of new mRNA translation.

    “This abnormally high level of Arc expression in Fmr1 knockout mice may be responsible for the enhanced mGluR–LTD observed in these animals and might explain, in part, why their LTD is independent of new mRNA translation62.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Hou, L. et al. Dynamic translational and proteasomal regulation of fragile X mental retardation protein controls mGluR-dependent long-term depression. Neuron 51, 441–454 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice, retrieval of fear memory leads to polyubiquitination and degradation of Shank proteins and correlates with a requirement for protein degradation in memory extinction.

    “In mice, the retrieval of fear memory was found to lead to the polyubiquitination and degradation of Shank proteins and to correlate with a requirement for protein degradation in memory extinction53.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Lee, S. H. et al. Synaptic protein degradation underlies destabilization of retrieved fear memory. Science 319, 1253–1256 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PtdIns(3,4,5)P3 binds and activates PDK1, which contributes to activation of Akt.

    “This then binds and activates phosphoinositide-dependent protein kinase (PDK1), which in turn contributes to activation of the serine/threonine protein kinase Akt proteins.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Han, J. M. & Sahin, M. TSC1/TSC2 signaling in the CNS. FEBS Lett. 585, 973–980 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss-of-function mutations in TSC1 or TSC2 in TSC result in deregulated mTOR signalling and abnormal neuronal protein synthesis.

    “Loss of function mutations in TSC1 or TSC2 that occur in tuberous sclerosis complex, result in deregulated mTOR signalling and abnormal neuronal protein synthesis”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] Kelleher, R. J. III & Bear, M. F. The autistic neuron: troubled translation? Cell 135, 401–406 (2008). source

      Not checked in the free run.

    • cites [69] Ehninger, D. et al. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nature Med. 14, 843–848 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of MEF2 decreases the number of excitatory synapses in wild-type neurons but not in Fmr1 knockout neurons.

    “activation of MEF2 leads to a decrease in the number of excitatory synapses in wild-type neurons, but not in Fmr1 knockout neurons”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Pfeiffer, B. E. et al. Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66, 191–197 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In fear conditioning, Tsc2+/- mice have a defect in distinguishing familiar and new contexts, which can be corrected by augmentation of mGluR5 signalling.

    “In a fear conditioning behavioural model, Tsc2+/− mice have a defect in distinguishing familiar and new contexts, a defect that can also be corrected by augmentation of mGluR5 signalling71.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Auerbach, B. D., Osterweil, E. K. & Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011). This paper shows that loss of function of either TSC1–TSC2 or FMRP disrupts activity-regulated mRNA translation and synaptic plasticity in opposite directions. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In the absence of FMRP, Arc protein level is abnormally high, so further activation of Arc transcription by MEF2 may not have much effect on synapse number.

    “However, in the absence of FMRP, the level of Arc protein is abnormally high, so that further activation of Arc transcription by MEF2 may not have much of an effect on synapse number.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Inactivating PTEN mutations lead to excessive PI(3)K-AKT and mTOR signalling, which may lead to abnormal protein synthesis and ultimately synaptic dysfunction and ASD.

    “Mutations that inactivate PTEN lead to excessive PI(3)K–AKT and mTOR signalling and in this way may lead to abnormal protein synthesis, and ultimately synaptic dysfunction and ASD.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mutations in PTEN, a negative regulator of PI(3)K-AKT signalling upstream of TSC1-TSC2, result in syndromic ASD.

  • May combine two claims.

    Premisecitation

    Newly synthesized BDNF is secreted from excitatory neurons and acts near its release site to regulate synaptic development and plasticity, including development of inhibitory synapses.

    “Newly synthesized BDNF is then secreted from excitatory neurons and functions near the site of release to regulate synaptic development and plasticity, including the development of inhibitory synapses30.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Hong, E. J., McCord, A. E. & Greenberg, M. E. A biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition. Neuron 60, 610–624 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Excessive mTOR activity leads to decreased protein synthesis and LTD deficiency in Tsc2+/- mice.

    “suggesting that excessive mTOR activity leads to decreased protein synthesis and LTD deficiency in Tsc2+/− mice71.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Auerbach, B. D., Osterweil, E. K. & Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011). This paper shows that loss of function of either TSC1–TSC2 or FMRP disrupts activity-regulated mRNA translation and synaptic plasticity in opposite directions. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many other FMRP targets are involved in synaptic plasticity, and there is significant overlap between FMRP targets and ASD candidate genes including NLGN3, NRXN1, SHANK3, PTEN, TSC1, and NF1.

    “Many other FMRP targets have been shown to be involved in synaptic plasticity, and there is significant overlap between FMRP targets and ASD candidate genes, including NLGN3, NRXN1, SHANK3, PTEN, TSC1 and NF123,33.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Bhakar, A. L., Dolen, G. & Bear, M. F. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012). source

      Not checked in the free run.

    • cites [33] Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    FMRP is a key regulator of activity-dependent mRNA translation and synaptic plasticity, and dysregulation of this pathway may contribute significantly to ASD phenotypes.

    “Taken together, these studies implicate FMRP as a key regulator of activity-dependent mRNA translation and synaptic plasticity and suggest that dysregulation of this pathway may contribute significantly to ASD phenotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BDNF binding to TrkB activates PI(3)K, which phosphorylates PtdIns(4,5)P2 to generate PtdIns(3,4,5)P3.

    “BDNF binding to TrkB activates the phosphatidylinositol-3-OH kinase (PI(3)K), which phosphorylates phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) at the 3′ position to generate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Han, J. M. & Sahin, M. TSC1/TSC2 signaling in the CNS. FEBS Lett. 585, 973–980 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tsc2+/- mice have deficient mGluR-LTD in the hippocampus but no defect in basal synaptic transmission.

    “Mice with a heterozygous loss of function mutation in Tsc2 (Tsc2+/−) have deficient mGluR–LTD in the hippocampus, but no defect in basal synaptic transmission.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Auerbach, B. D., Osterweil, E. K. & Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011). This paper shows that loss of function of either TSC1–TSC2 or FMRP disrupts activity-regulated mRNA translation and synaptic plasticity in opposite directions. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Findings of deficient mGluR-LTD in Tsc1/Tsc2 deletion mice contrast with Fmr1 knockout mice, which have increased mGluR-LTD and excessive protein synthesis.

    “These findings of deficient mGluR–LTD in mice with deletions in Tsc1 or Tsc2 are in contrast with Fmr1 knockout mice, which have increased mGluR–LTD and excessive protein synthesis57.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Osterweil, E. K., Krueger, D. D., Reinhold, K. & Bear, M. F. Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J. Neurosci. 30, 15616–15627 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of mTOR in Tsc2+/- mice restored mGluR-LTD and normalized protein synthesis rates to wild-type levels.

    “Inhibition of mTOR in Tsc2+/− mice restored mGluR–LTD and normalized protein synthesis rates to that of wild-type mice rates”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Auerbach, B. D., Osterweil, E. K. & Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011). This paper shows that loss of function of either TSC1–TSC2 or FMRP disrupts activity-regulated mRNA translation and synaptic plasticity in opposite directions. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TSC is caused by mutations in TSC1 or TSC2, which encode tumour suppressor proteins forming the TSC1-TSC2 complex that regulates protein synthesis in many mammalian cell types including neurons.

    “This disorder is caused by mutations in TSC1 or TSC2 that encode tumour suppressor proteins which form the complex TSC1–TSC2 that regulate protein synthesis in a wide range of mammalian cell types, including neurons67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Han, J. M. & Sahin, M. TSC1/TSC2 signaling in the CNS. FEBS Lett. 585, 973–980 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Phosphorylation of TSC2 leads to Rheb activation, which triggers mTOR activation, contributing to protein synthesis.

    “Thus, phosphorylation of TSC2 leads to Rheb activation, which in turn triggers activation of the protein kinase mTOR, contributing to the activation of protein synthesis (Fig. 4)67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Han, J. M. & Sahin, M. TSC1/TSC2 signaling in the CNS. FEBS Lett. 585, 973–980 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Proper synaptic function in response to neuronal activity requires tight regulation of protein synthesis at synapses; TSC1/TSC2 and Fmr1 mutations disrupt this balance in opposite directions, leading to synaptic plasticity defects that may contribute to ASD phenotypes.

    “These findings suggest that, for proper synaptic function in response to neuronal activity, protein synthesis at synapses is tightly regulated, and TSC1 and TSC2 as well as Fmr1 mutations disrupt this balance in opposite directions, leading to defects in synaptic plasticity that may contribute to ASD phenotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Inhibition of mGluR5 in Fmr1 knockout mice corrects excessive protein synthesis and mGluR5-dependent LTD; augmentation of mGluR5 signalling restores protein synthesis and mGluR-dependent LTD in Tsc2+/- mice.

    “Whereas inhibition of mGluR5 in Fmr1 knockout mice corrects excessive protein synthesis and mGluR5-dependent LTD, augmentation of mGluR5 signalling by a positive allosteric modulator restored protein synthesis and mGluR-dependent LTD in Tsc2+/− mice71.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Auerbach, B. D., Osterweil, E. K. & Bear, M. F. Mutations causing syndromic autism define an axis of synaptic pathophysiology. Nature 480, 63–68 (2011). This paper shows that loss of function of either TSC1–TSC2 or FMRP disrupts activity-regulated mRNA translation and synaptic plasticity in opposite directions. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    MECP2 is a key regulator of chromatin architecture and gene expression that modulates synaptic development, function, and plasticity.

    “Together with the molecular studies of MECP2 function, these electrophysiological experiments suggest that MECP2 is a key regulator of chromatin architecture and gene expression that modulates synaptic development, function and plasticity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In mice, this missense mutation leads to increased Ca2+ currents and loss of voltage-dependent channel inactivation.

    “Studies in mice indicate that this missense mutation leads to increased Ca2+ currents and loss of voltage-dependent channel inactivation31,77.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] Splawski, I. et al. CaV1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19–31 (2004). source

      Not checked in the free run.

    • cites [77] Barrett, C. F. & Tsien, R. W. The Timothy syndrome mutation differentially affects voltage- and calcium-dependent inactivation of CaV1.2 L-type calcium channels. Proc. Natl Acad. Sci. USA 105, 2157–2162 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice expressing a truncated Mecp2 variant lacking the C-terminal region have multiple defects in learning and memory and synaptic plasticity.

    “mice expressing a truncated Mecp2 variant, lacking the C-terminal region, have multiple defects in learning and memory, as well as synaptic plasticity88.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Moretti, P. et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319–327 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ser421Ala knock-in mice and wild-type mice express equivalent levels of MECP2, but Ser421Ala mice display increased dendritic complexity and increased inhibitory synaptic strength in the cortex.

    “The Ser421Ala knock-in mice and wild-type mice express equivalent levels of MECP2, but the Ser421Ala knock-in mice display increased dendritic complexity and increased inhibitory synaptic strength in the cortex80.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Cohen, S. et al. Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72, 72–85 (2011). This paper demonstrates the importance of activity-dependent regulation of MECP2 in the control of synapse development and behaviour. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    UBE3A expression in the nervous system is kept in check through imprinting and is further regulated by neuronal activity.

    “Thus, the level of the gene's expression in the nervous system is kept in check through imprinting and is further regulated by neuronal activity.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The paternally inherited allele of UBE3A is imprinted and specifically silenced in the brain.

  • May combine two claims.

    Interpretationreasoning

    Dysregulation of at least some MECP2 functions likely leads to Rett syndrome and possibly other ASD.

    “It is likely that the dysregulation of at least some of MECP2 functions lead to Rett syndrome and possibly other ASD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Compared to wild-type neurons, Timothy syndrome neurons had impaired Ca2+ channel inactivation and a significant increase in sustained intracellular Ca2+ elevation after membrane depolarization.

    “Compared with wild-type neurons, the Timothy syndrome neurons had impaired Ca2+ channel inactivation and a significant increase in sustained intracellular Ca2+ elevation after membrane depolarization.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Pasca, S. P. et al. Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome. Nature Med. 17, 1657–1662 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of MECP2 changes the balance between inhibition and excitation in the brain, altering the neuronal response to sensory experience.

    “There is also evidence that loss of MECP2 changes the balance between inhibition and excitation in the brain, altering the neuronal response to sensory experience.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [86] Dani, V. S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 102, 12560–12565 (2005). source

      Not checked in the free run.

    • cites [87] Chao, H. T., Zoghbi, H. Y. & Rosenmund, C. MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65 (2007). source

      Not checked in the free run.

    • cites [88] Moretti, P. et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319–327 (2006). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During late development when visual experience is required, synapses in the retinogeniculate circuit are abnormal in Mecp2 knockout mice, resulting in impaired synaptic plasticity on visual deprivation.

    “during a late stage of development when visual experience is required for modulation and maintenance of the retinogeniculate circuit, the synapses that form on the neurons within this circuit are abnormal in Mecp2 knockout mice, resulting in impaired synaptic plasticity on visual deprivation85.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Noutel, J., Hong, Y. K., Leu, B., Kang, E. & Chen, C. Experience-dependent retinogeniculate synapse remodeling is abnormal in MeCP2-deficient mice. Neuron 70, 35–42 (2011). source

      Not checked in the free run.

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

    Interpretationcitation

    Loss of experience-dependent induction of UBE3A mRNA during postnatal development may contribute to Angelman syndrome, and increased activity-dependent UBE3A expression may underlie some forms of ASD.

    “it has therefore been suggested that a loss of experience-dependent induction of the UBE3A mRNA during post-natal development may contribute to Angelman syndrome, and increased activity-dependent UBE3A expression may underlie some forms of ASD89.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Greer, P. L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc. Cell 140, 704–716 (2010). This study provides insight into the molecular mechanisms underlying Angelman syndrome and the role of neuronal activity in regulating UBE3A and its targets. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Ube3a protein regulates excitatory-inhibitory balance during brain development, and when its expression is perturbed ASD may occur.

    “These studies suggest that Ube3a protein regulates excitatory–inhibitory balance during brain development and that when the level of expression is perturbed ASD may occur.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [90] Jiang, Y. H. et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21, 799–811 (1998). source

      Not checked in the free run.

    • cites [91] Yashiro, K. et al. Ube3a is required for experience-dependent maturation of the neocortex. Nature Neurosci. 12, 777–783 (2009). source

      Not checked in the free run.

    • cites [92] Wallace, M. L., Burette, A. C., Weinberg, R. J. & Philpot, B. D. Maternal loss of Ube3a produces an excitatory/inhibitory imbalance through neuron type-specific synaptic defects. Neuron 74, 793–800 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Mecp2 knockout mice, whole-cell patch clamp recordings in the somatosensory cortex revealed decreased excitatory synaptic drive and increased inhibitory drive onto L5 pyramidal cells.

    “In Mecp2 knockout mice, whole-cell patch clamp recordings in the somatosensory cortex revealed decreased excitatory synaptic drive and increased inhibitory drive onto L5 pyramidal cells86.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Dani, V. S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 102, 12560–12565 (2005). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Activity-dependent phosphorylation of MECP2 regulates synapse development and function and behavioural responses to environmental stimuli.

    “These findings indicate that activity-dependent phosphorylation of MECP2 regulates synapse development and function and behavioural responses to environmental stimuli.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Cohen, S. et al. Genome-wide activity-dependent MeCP2 phosphorylation regulates nervous system development and function. Neuron 72, 72–85 (2011). This paper demonstrates the importance of activity-dependent regulation of MECP2 in the control of synapse development and behaviour. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice with a deletion in the maternal copy of Ube3A have impairments in learning and in the LTP form of synaptic plasticity.

    “Mice that carry a deletion in the maternal copy of Ube3A have impairments in learning and in the LTP form of synaptic plasticity90.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Jiang, Y. H. et al. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21, 799–811 (1998). source

      Not checked in the free run.

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

    Premisecitation

    References 47-49 report mouse models of Shank mutations that demonstrate Shanks' role in regulating excitatory neurotransmission.

    “References 47–49 report the studies of mouse models of Shank mutations to demonstrate the role of Shanks in regulating excitatory neurotransmission.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [47] Peca, J. et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature 472, 437–442 (2011). source

      Not checked in the free run.

    • cites [48] Schmeisser, M. J. et al. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2. Nature 486, 256–260 (2012). source

      Not checked in the free run.

    • cites [49] Won, H. et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486, 261–265 (2012). References 47–49 demonstrate the role of Shanks in regulating excitatory neurotransmission. source

      Not checked in the free run.

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

    Premisecitation

    Reference 34 provides evidence that genetic mutations linked to autism may disrupt activity-dependent gene expression programs.

    “This paper provides evidence for the hypothesis that genetic mutations associated with autism may disrupt activity-dependent gene expression programs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Morrow, E. M. et al. Identifying autism loci and genes by tracing recent shared ancestry. Science 321, 218–223 (2008). This paper provides evidence for the hypothesis that genetic mutations associated with ASD may disrupt activity-dependent gene expression programs. source

      Not checked in the free run.

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

    Premisecitation

    Reference 41 reports that neuroligins have a crucial role in activity-dependent synapse maturation and that this pathway is dysregulated by ASD-associated neuroligin mutations.

    “This study reports the crucial role for neuroligins in activity-dependent synapse maturation and how this pathway is dysregulated by ASD-associated mutations in neuroligin.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Chubykin, A. A. et al. Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54, 919–931 (2007). This study reports the crucial role for neuroligins in activity-dependent synapse maturation and how this pathway is dysregulated by ASD-associated mutations in neuroligin. source

      Not checked in the free run.

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

    Premisecitation

    References 7-10 used exome and whole-genome sequencing to show the importance of rare mutations in ASD and to identify new genetic mutations linked to ASD.

    “References 7– 10 use exome and entire genome sequencing to demonstrate the importance of rare mutations in ASD and identify new genetic mutations associated with ASD.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [7] Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012). source

      Not checked in the free run.

    • cites [8] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source

      Not checked in the free run.

    • cites [9] O'Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genet. 43, 585–589 (2011). source

      Not checked in the free run.

    • cites [10] Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012). References 7–10 demonstrate the ability of new sequencing technologies to significantly advance our understanding of the genetic basis of ASD. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    ASD-associated mutations in the Ras-MAPK pathway may disrupt activity-dependent synaptic development and plasticity by changing activity-regulated mRNA translation or gene transcription.

    “mutations in this pathway that are associated with ASD may be disrupting activity-dependent synaptic development and plasticity by altering activity-regulated mRNA translation or gene transcription.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Reference 43 shows in Aplysia that the neurexin-neuroligin interaction controls activity-dependent synaptic development and plasticity, and that an ASD-associated neuroligin mutation disrupts this process.

    “Using the Aplysia model system, this study demonstrates that the neurexin-neuroligin interaction regulates activity-dependent synaptic development and plasticity, a process that is dysregulated by an ASD-associated mutation in neuroligin.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Choi, Y. B. et al. Neurexin-neuroligin transsynaptic interaction mediates learning-related synaptic remodeling and long-term facilitation in Aplysia. Neuron 70, 468–481 (2011). Using the Aplysia model, this study demonstrates that the neurexin–neuroligin interaction regulates activity-dependent synaptic development and plasticity, a process that is dysregulated by an ASD-associated mutation in neuroligin. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Ras-MAPK pathway is required for protein synthesis regulated by activity, transcription of genes dependent on activity, and synaptic plasticity mediated by mGluR.

    “As the Ras–MAPK signalling pathway is crucial for activity-regulated protein synthesis, activity-dependent gene transcription and mGluR dependent synaptic plasticity23,25,95”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Bhakar, A. L., Dolen, G. & Bear, M. F. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012). source

      Not checked in the free run.

    • cites [25] Dolmetsch, R. E., Pajvani, U., Fife, K., Spotts, J. M. & Greenberg, M. E. Signaling to the nucleus by an L-type calcium channel–calmodulin complex through the MAP kinase pathway. Science 294, 333–339 (2001). source

      Not checked in the free run.

    • cites [95] Kelleher, R. J. III, Govindarajan, A., Jung, H. Y., Kang, H. & Tonegawa, S. Translational control by MAPK signaling in long-term synaptic plasticity and memory. Cell 116, 467–479 (2004). source

      Not checked in the free run.

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

    Interpretationcitation

    Those studies show that new sequencing technologies can greatly advance knowledge of the genetic basis of ASD.

    “These studies demonstrate the ability of new sequencing technologies to significantly advance our understanding of the genetic basis of ASD.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [7] Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485, 237–241 (2012). source

      Not checked in the free run.

    • cites [8] Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485, 242–245 (2012). source

      Not checked in the free run.

    • cites [9] O'Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nature Genet. 43, 585–589 (2011). source

      Not checked in the free run.

    • cites [10] Kong, A. et al. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471–475 (2012). References 7–10 demonstrate the ability of new sequencing technologies to significantly advance our understanding of the genetic basis of ASD. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Dysregulation of Arc levels and AMPA receptor expression at synapses may contribute to ASD phenotypes in Angelman syndrome and possibly ASD involving CNVs on chromosome 15.

    “Thus, the dysregulation of Arc levels and AMPA receptor expression at synapses may contribute to the ASD phenotypes observed in Angelman syndrome and possibly ASD that involve CNVs on chromosome 15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Greer, P. L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc. Cell 140, 704–716 (2010). This study provides insight into the molecular mechanisms underlying Angelman syndrome and the role of neuronal activity in regulating UBE3A and its targets. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in several components of the Ras-MAPK pathway have been associated with ASD, including rare mutations in HRAS, MAP2K2 and SYNGAP1, and with syndromes that have ASD features and mutations in NF1, MAP2K1, MAP2K2.

    “Mutations in multiple components of this pathway have recently been found to be associated with ASD, including rare mutations in HRAS, MAP2K2 and SYNGAP1, and with syndromes with ASD features (that have mutations in NF1, MAP2K1, MAP2K2)93,94.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [93] Kelleher, R. J. III et al. High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. PLoS ONE 7, e35003 (2012). source

      Not checked in the free run.

    • cites [94] Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased Arc expression in the absence of UBE3A results in decreased AMPA receptor cell surface expression and decreased AMPA receptor-mediated currents.

    “The increased level of Arc expression in the absence of UBE3A results in decreased AMPA receptor cell surface expression and a decrease in the AMPA receptor-mediated currents89.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Greer, P. L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc. Cell 140, 704–716 (2010). This study provides insight into the molecular mechanisms underlying Angelman syndrome and the role of neuronal activity in regulating UBE3A and its targets. source

      Not checked in the free run.

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

    Premisecitation

    Reference 89 gives insight into the molecular mechanisms of Angelman syndrome and the role of neuronal activity in regulating Ube3A and its targets.

    “This study provides insight into the molecular mechanisms underlying Angelman syndrome and the role of neuronal activity in regulating Ube3A and its targets.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Greer, P. L. et al. The Angelman syndrome protein Ube3A regulates synapse development by ubiquitinating Arc. Cell 140, 704–716 (2010). This study provides insight into the molecular mechanisms underlying Angelman syndrome and the role of neuronal activity in regulating UBE3A and its targets. source

      Not checked in the free run.

87 of 87

  • The paper relies on this without support.

    Findings from animal models (rodents, Aplysia) about the synaptic and behavioural effects of ASD-associated mutations are informative about the molecular basis of human ASD.

    “These studies indicate that particular ASD mutations in neurexins or neuroligins disrupt excitatory or inhibitory neurotransmission in the brain in specific ways and suggest that modelling ASD-associated mutations in mice will be important for elucidating how each mutation affects synaptic function and give rise to ASD.”

  • The paper relies on this without support.

    The activity-dependent signalling pathways that regulate synapse development and plasticity in model organisms operate similarly in humans.

    “A cardinal feature of human brain development is that sensory, cognitive and emotional experiences shape synapse and neural-circuit development.”

  • The paper relies on this without support.

    Phelan-McDermid syndrome is an ASD resulting from a microdeletion that includes heterozygous loss of SHANK3.

    “In particular, Phelan-McDermid syndrome is an ASD that results from a microdeletion that includes heterozygous loss of SHANK3.”

  • The paper relies on this without support.

    Long-lasting synaptic plasticity elicited by glutamate binding to NMDA receptors or group 1 mGluRs typically requires protein synthesis mediated by mRNAs and ribosomes localized near synapses.

    “Long-lasting forms of synaptic plasticity that are elicited by glutamate binding to NMDA receptors or group 1 mGluRs, typically require protein synthesis that is mediated by mRNAs and ribosomes that are localized near synapses.”

  • The paper relies on this without support.

    Long-lasting NMDA receptor-dependent LTP and LTD have a delayed requirement for protein synthesis, whereas mGluR-dependent LTD requires protein synthesis that occurs within minutes.

    “Long-lasting NMDA receptor-dependent LTP and LTD have a delayed requirement for protein synthesis, whereas mGluR-dependent LTD requires protein synthesis that occurs within minutes.”

  • The paper relies on this without support.

    Fragile X syndrome is caused by mutations in FMR1, resulting in decreased expression of the RNA-binding protein FMRP.

    “Fragile X syndrome is caused by mutations in FMR1, resulting in decreased expression of the RNA-binding protein FMRP.”

  • The paper relies on this without support.

    Arc protein promotes internalization of AMPA receptors at excitatory synapses.

    “The protein encoded by this activity-regulated gene promotes the internalization of AMPA receptors at excitatory synapses.”

  • The paper relies on this without support.

    During early postnatal brain development, neuronal activity promotes changes in glutamate receptor subtype that are required for proper maturation of excitatory thalamocortical synapses in the somatosensory cortex.

    “During early post-natal brain development, neuronal activity promotes changes in glutamate receptor subtype that are required for proper maturation of excitatory thalamocortical synapses in the somatosensory cortex.”

  • The paper relies on this without support.

    TSC is characterized by benign tumours in multiple organs and a high penetrance of ASD.

    “TSC is characterized by benign tumours in multiple organs as well as a high penetrance of ASD.”

  • The paper relies on this without support.

    BDNF is a major activator of TSC1-TSC2 signalling in neurons; BDNF binds TrkB and mediates many aspects of brain development and function.

    “One major activator of TSC1–TSC2 signalling in neurons is brain-derived neurotrophic factor (BDNF), a secreted protein that binds to the receptor tyrosine kinase TrkB on the surface of neurons and thereby mediates many aspects of brain development and function.”

  • The paper relies on this without support.

    Neuronal activity potently induces Bdnf transcription in excitatory neurons.

    “Neuronal activity potently induces Bdnf transcription in excitatory neurons.”

  • The paper relies on this without support.

    Mutations in PTEN, a negative regulator of PI(3)K-AKT signalling upstream of TSC1-TSC2, result in syndromic ASD.

    “mutations in PTEN, a negative regulator of PI(3)K–AKT signalling upstream of TSC1–TSC2, also result in syndromic ASD.”

  • The paper relies on this without support.

    Neuronal activity regulates programs of gene expression in the nucleus that modulate synaptic development and plasticity.

    “neuronal activity regulates programs of gene expression in the nucleus that modulate synaptic development and plasticity.”

  • The paper relies on this without support.

    L-type calcium channels are voltage-gated and open upon membrane depolarization.

    “The L-type calcium channels are voltage-gated and thus open upon membrane depolarization.”

  • The paper relies on this without support.

    Mutations in MECP2 lead to Rett syndrome, an ASD characterized by impaired language development, loss of social engagement, stereotyped hand movements, seizures, and motor-system disabilities.

    “Mutations in MECP2 lead to Rett syndrome, one form of ASD characterized by impaired language development, loss of social engagement, stereotyped hand movements, seizures and motor-system disabilities.”

  • The paper relies on this without support.

    MECP2 binds methylated cytosines in DNA and seems to function mainly as a transcriptional repressor.

    “MECP2 binds methylated cytosines within DNA and seems to function mainly as a transcriptional repressor.”

  • The paper relies on this without support.

    MECP2 expression in post-mitotic neurons is about tenfold higher than in other cell types.

    “The level of MECP2 expression in post-mitotic neurons is about tenfold higher than in other cell types”

  • The paper relies on this without support.

    MECP2 expression in mature neurons is similar to that of core histones, and MECP2 is bound broadly across the genome.

    “the level of MECP2 expression in mature neurons is similar to that of core histones, and MECP2 is bound broadly across the genome.”

  • The paper relies on this without support.

    Angelman syndrome is characterized by motor dysfunction, speech impairment, seizures, and high prevalence of autism, and is caused by deletions of the maternally inherited allele of chromosomal region 15q11-q13.

    “Angelman syndrome is characterized by motor dysfunction, speech impairment, seizures and high prevalence of autism, and is caused by deletions of the maternally inherited allele of chromosomal region 15q11–q13.”

  • The paper relies on this without support.

    Loss of UBE3A function in this chromosomal region is by itself sufficient to cause Angelman syndrome.

    “The loss of UBE3A function in this chromosomal region is by itself sufficient to cause Angelman syndrome.”

  • The paper relies on this without support.

    CNVs that lead to duplications and triplications of the same chromosomal region are associated with ASD.

    “CNVs that lead to duplications and triplications of the same chromosomal region are associated with ASD.”

  • The paper relies on this without support.

    The paternally inherited allele of UBE3A is imprinted and specifically silenced in the brain.

    “the paternally inherited allele of UBE3A is imprinted, and specifically silenced in the brain.”

  • The paper relies on this without support.

    UBE3A is a member of a family of E3 ubiquitin ligases that catalyse ubiquitination of substrates, often leading to proteasomal degradation.

    “UBE3A is a member of a family of E3 ubiquitin ligases, which catalyse the ubiquitination of substrates, often leading to the degradation of the ubiquitinated substrate by the proteasome.”
23 of 23

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?

  • 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 [18]

    The ‘Neuronal activity regulates synapses and circuits’ section says activity regulates synaptic development and plasticity, altering neural circuits. The Abstract also links disrupted activity-dependent synapse development to altered neurotransmission. But the paper does not establish that disruption of any one of the named processes necessarily produces network-wide connectivity deficits; its broader causal discussion remains qualified. (LLM, conf=0.85)

    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 [18]

    The 'Synaptic proteins implicated in ASD > Shanks' section (page not supplied) links synaptic morphology and function to ASD-associated mutations, supporting the ASD portion. The paper also says that people with ASD often have intellectual disability and seizures, but it does not establish the claimed association of dendritic changes with schizophrenia, intellectual disability and epilepsy as separate disorders, or document all the specified changes in spine number, shape and plasticity. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Neuronal depolarization communication proceeds through various signaling cascades and regulates intranuclear events such as enhancer recruitment, transcription factor activation, and alternative pre-mRNA splicing.

    “Communication of neuronal depolarization proceeds by a variety of signaling cascades and regulates intranuclear events such as enhancer recruitment (Kim et al., 2010), transcription factor activation (Ebert and Greenberg, 2013) and alternative pre-mRNA splicing (Li et al., 2007).”

    From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Ebert and Greenberg, 2013

  • ASD-associated mutations that alter neurotransmission ultimately disrupt activity-dependent signaling to the nucleus.

    “Likewise, ASD-associated mutations that alter neurotransmission ultimately disrupt activity-dependent signaling to the nucleus (Ebert and Greenberg, 2013).”

    From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Ebert and Greenberg, 2013

  • Several genes associated with ASD are regulated by neuronal activity.

    “several genes associated with ASD are regulated by neuronal activity 20”

    From Progress toward treatments for synaptic defects in autism (2013) · cites this paper as [20]

Cites

1 retracted

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Ebert, D. H., & Greenberg, M. E.
Affiliations
Harvard University (US)
Corresponding author
Greenberg, Michael E.
ORCID
Greenberg, Michael E.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2013-01-16
Volume
493
Issue
7432
Pages
327-337
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature11860
PMC
PMC3576027
OpenAlex
W2082023836
Cited by
666
References
100
Citations by year
2026: 21 · 2025: 27 · 2024: 45 · 2023: 46 · 2022: 37 · 2021: 44 · 2020: 86 · 2019: 45 · 2018: 56 · 2017: 54 · 2016: 57 · 2015: 54 · 2014: 55 · 2013: 37 · 2012: 1
FWCI
8.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health (5r01ns048276-15)
  • National Institute of Mental Health (K08MH090306, K08MH90306)
  • National Institute of Neurological Disorders and Stroke (R01-NS-048276)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
autism spectrum disorder, synaptic plasticity, synaptic development, post-translational modification, dendritic protein synthesis, gene transcription, neural circuits, autism etiology
MeSH terms
Child, Child Development Disorders, Pervasive, Gene Expression Regulation, Humans, Neuronal Plasticity, Neurons, Synapses, Signal Transduction

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review