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Cited by 385Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchAutism Spectrum Disorder Research

Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses

Open access
Clement, James P., Aceti, Massimiliano, Creson, Thomas K., Ozkan, Emin D., Shi, Yulin, Reish, Nicholas J., Almonte, Antoine G., Miller, Brooke H. +4 more·2012·Cell
DOI 10.1016/j.cell.2012.08.045PMC PMC3500766
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Abstract

SUMMARY Mutations that cause Intellectual Disability (ID) and Autism Spectrum Disorder (ASD) are commonly found in genes that encode for synaptic proteins. However, it remains unclear how mutations that disrupt synapse function impact intellectual ability. In the SYNGAP1 mouse model of ID/ASD, we found that dendritic spine synapses develop prematurely during the early postnatal period. Premature spine maturation dramatically enhanced excitability in the developing hippocampus, which corresponded with the emergence of behavioral abnormalities. Inducing SYNGAP1 mutations after critical developmental windows closed had minimal impact on spine synapse function, while repairing these pathogenic mutations in adulthood did not improve behavior and cognition. These data demonstrate that SynGAP protein acts as a critical developmental repressor of neural excitability that promotes the development of life-long cognitive abilities. We propose that the pace of dendritic spine synapse maturation in early life is a critical determinant of normal intellectual development.

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Registry

Crossref · 10.1016/j.cell.2012.08.045

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 66 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Loss of this essential glutamatergic synapse repressor dramatically disrupted E/I balance in neural networks supporting cognition and behavior.

    “Loss of this essential glutamatergic synapse repressor dramatically disrupted E/I balance in neural networks that support cognition and behavior and these effects were linked to life-long intellectual disability.”
    Quote in the paperSubstantial claim
  • Findingown data

    The increased excitability corresponded with emergence of behavioral abnormalities.

    “Premature spine maturation dramatically enhanced excitability in the developing hippocampus, which corresponded with the emergence of behavioral abnormalities.”
    Quote in the paperSubstantial claim
  • Findingown data

    Premature spine maturation greatly increased excitability in the developing hippocampus.

    “Premature spine maturation dramatically enhanced excitability in the developing hippocampus, which corresponded with the emergence of behavioral abnormalities.”
    Quote in the paperSubstantial claim
  • Findingown data

    In this study, the mouse model of human SYNGAP1 haploinsufficiency had glutamatergic synapses that matured at an accelerated rate during the first few weeks of neonatal development.

    “In this study, we found that a mouse model of human SYNGAP1 haploinsufficiency had glutamatergic synapses that matured at an accelerated rate during the first few weeks of neonatal development.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mouse SYNGAP1 haploinsufficiency model recapitulates human SYNGAP1 haploinsufficiency and its cognitive/behavioral phenotype.
  • Findingown data

    At PND14, there was a decrease in spatial volume occupied by individual DGN dendritic trees in Hets.

    “While dendritic arborization was unchanged in SYNGAP1 Hets (not shown), we did observe a decrease in the spatial volume occupied by individual DGN dendritic trees (Fig. 3F-G).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 11

  • May combine two claims.

    Findingown data

    Synaptic disruptions first seen at PND14 were largely specific to postsynaptic function, with no changes in MPP release probability or intrinsic spiking of DGNs.

    “Synaptic disruptions first seen at PND 14 were largely specific to postsynaptic function because we did not detect changes in MPP release probability (Fig. 2E) or intrinsic spiking of DGNs at this age (Fig. 2F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SYNGAP1 haploinsufficiency alters dendritic spine size in early development, confirmed by Thy1-GFP Hets.

    “Importantly, we confirmed that SYNGAP1 haploinsufficiency alters dendritic spine size in early development by characterizing these structures from internally perfused and fixed Thy1-GFP SYNGAP1 Hets (Figure S2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    At PND9, SynGAP mutants had normal dendritic spine structure, but spines became larger relative to WT by PND14.

    “At PND9, SynGAP mutants had normal dendritic spine structure (Fig. 3A), but spines became larger relative to WT by PND14 (Fig. 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Disruption to spine head size altered distribution of spine classes in Het mice, resulting in more mushroom-type and fewer stubby spines beginning in second postnatal week.

    “The disruption to spine head size altered the distribution of spine classes in Het mice, resulting in more mushroom-type spines and fewer stubby spines beginning in the second postnatal week (Fig. 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In Het mice, synaptic transmission in medial perforant path of dentate gyrus was normal at ~PND9 but increased dramatically by PND14.

    “Synaptic function was normal at very young ages (~PND9), but transmission increased dramatically in Het mice by PND14 (Fig. 1C-D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Synaptic transmission in Schaeffer Collateral pathway in Area CA1 was abnormally strong in early development but not in adult Hets.

    “Indeed, we found that synaptic transmission in the Schaeffer Collateral pathway in Area CA1 was also abnormally strong in early development, but not in adult Hets (Fig. 5D and Figure S4)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Presence of LoxP-stop cassette resulted in behavioral abnormalities similar to conventional SYNGAP1 Hets, and presence of CRE-ERt2 had minimal impact on behaviors tested.

    “The presence of the LoxP-stop cassette again resulted in behavioral abnormalities similar to that seen in our conventional SYNGAP1 Hets and the presence of CRE-ERt2 had minimal impact on the behaviors tested (Fig. 8B-D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This effect was not observed in PND1 virus-injected animals or conventional adult Hets.

    “This effect was not observed in either PND1 virus-injected animals (Figure S5) or in conventional adult Hets (Fig. 2F)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both Cre+ and Cre− SYNGAP1 LoxP-Stop Hets exhibited increased time in open arm of elevated plus maze, increased open field activity levels.

    “Specifically, both Cre+ and Cre− SYNGAP1 LoxP-Stop Hets exhibited increased time in the open arm of the elevated plus maze, increased open field activity levels and the”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Motility rates did not drop in Het mice, as they already displayed adultlike motility rates by end of second postnatal week.

    “However, motility rates did not drop in Het mice, as they already displayed adultlike motility rates by the end of the second postnatal week (Fig. 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    WT mice were able to discriminate between similar contexts A and B, learning to freeze less in context B.

    “WT mice were also able to discriminate between the similar contexts A and B, as they learned to freeze less in context B (Fig. 6C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Circuit-level excitability changes in neonates were accompanied by a reduced seizure threshold and elevated open field activity.

    “These circuit-level excitability changes in neonates were accompanied by a reduced seizure threshold and elevated activity in the open field arena, suggesting that abnormal synapse maturation is directly altering behavioral performance and cognition.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Disruption of excitatory/inhibitory balance is a common neurophysiological phenotype in many brain disorders including ID and ASD.

    “Disruption of excitatory/inhibitory (E/I) balance is emerging as a common neurophysiological phenotype common to many brain disorders, including ID and ASD”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rubenstein and Merzenich, 2003 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    SynGAP acts as a critical developmental repressor of neural excitability that promotes development of life-long cognitive abilities.

    “These data demonstrate that SynGAP protein acts as a critical developmental repressor of neural excitability that promotes the development of life-long cognitive abilities.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The mouse SYNGAP1 haploinsufficiency model recapitulates human SYNGAP1 haploinsufficiency and its cognitive/behavioral phenotype.

  • May combine two claims.

    Interpretationreasoning

    De novo mutations disrupting SYNGAP1 are highly pathogenic and selectively impact brain function.

    “Thus, de novo mutations that disrupt SYNGAP1 are highly pathogenic and selectively impact brain function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Adult SynGAP heterozygous knockout mice have profound cognitive abnormalities despite lack of pervasive functional synaptic defects.

    “Despite the lack of pervasive functional synaptic defects in adulthood, these animals have profound cognitive abnormalities”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Guo et al., 2009 source

      Not checked in the free run.

    • cites Komiyama et al., 2002 source

      Not checked in the free run.

    • cites Muhia et al., 2010 source

      Not checked in the free run.

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

    Premisecitation

    Depending on the SynGAP variant expressed, SynGAP can either stimulate or suppress dendritic spine synapse function.

    “depending on the variant expressed, SynGAP can either stimulate (Rumbaugh et al., 2006) or suppress dendritic spine synapse function (McMahon et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Rumbaugh et al., 2006 source

      Not checked in the free run.

    • cites McMahon et al., 2012 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SYNGAP1 encodes a synaptic RasGAP (SynGAP) largely localized to dendritic spines in neocortical pyramidal neurons, where it suppresses signaling linked to NMDAR-mediated plasticity and AMPAR membrane insertion.

    “SYNGAP1 encodes a synaptic RasGAP (SynGAP) that is largely localized to dendritic spines in neocortical pyramidal neurons (Chen et al., 1998; Kim et al., 1998; Zhang et al., 1999), where it suppresses signaling pathways linked to NMDA receptor (NMDAR) mediated synaptic plasticity and AMPA receptor (AMPAR) membrane insertion”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Chen et al., 1998 source

      Not checked in the free run.

    • cites Kim et al., 1998 source

      Not checked in the free run.

    • cites Zhang et al., 1999 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    All identified patients with SYNGAP1 haploinsufficiency have moderate to severe ID, and some also have ASD.

    “All identified patients with SYNGAP1 haploinsufficiency have moderate to severe forms of ID, and several of these patients also have an ASD”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Hamdan et al., 2011a

      Not checked in the free run.

    • cites Pinto et al., 2010 source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Patients with SYNGAP1 haploinsufficiency present with non-syndromic ID, with no physical abnormalities outside the cognitive/behavioral domain.

    “Interestingly, these patients present with non-syndromic ID, as there are no physical abnormalities other than those observed in the cognitive/behavioral domain.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Changes to the inhibitory system may represent a compensatory response to increased excitation caused by elevated postsynaptic dendritic spine synapse AMPAR function.

    “these data suggest the intriguing possibility that changes to the inhibitory system represent a compensatory response to increased excitation caused by elevated postsynaptic dendritic spine synapse AMPAR function in these neurons”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Increasing neural excitation is sufficient to disrupt cognition and sociability.

    “Recently, it was demonstrated that increasing neural excitation is sufficient to disrupt cognition and sociability”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yizhar et al., 2011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adult SynGAP heterozygous knockout mice are reported to have normal synaptic transmission and only modest defects in synaptic plasticity.

    “Interestingly, adult SynGAP Heterozygous knockout mice (Hets), which model human SYNGAP1 haploinsufficiency and offer construct validity, are reported to have normal synaptic transmission and only modest defects in synaptic plasticity”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Kim et al., 2003 source

      Not checked in the free run.

    • cites Komiyama et al., 2002 source

      Not checked in the free run.

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

    Premisecitation

    Deleterious mutations in synaptic proteins are linked to ID and ASD, and many animal models show deficits in synapse structure and/or function.

    “Deleterious mutations in synaptic proteins are linked to these disorders and many animal models display deficits related to synapse structure and/or function”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gauthier et al., 2011 source

      Not checked in the free run.

    • cites Gilman et al., 2011 source

      Not checked in the free run.

    • cites Guilmatre et al., 2009 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The LoxP-STOP cassette would be expected to cause truncation of full-length protein, which is known to inactivate SynGAP.

    “This cassette would be expected to cause a truncation of full-length protein, which is known to inactivate SynGAP (Rumbaugh et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rumbaugh et al., 2006 source

      Not checked in the free run.

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

    Premisecitation

    SynGAP's broad action on dendritic spine signaling arises from its central location in the NMDAR complex and its promiscuous GAP domain that can regulate various small G-proteins.

    “This broad action of SynGAP on dendritic spine signaling arises from its central location in the NMDAR complex (Kennedy et al., 2005) and its endowment with a promiscuous GAP domain that can regulate a variety of small G-proteins (Krapivinsky et al., 2004; Pena et al., 2008).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kennedy et al., 2005 source

      Not checked in the free run.

    • cites Krapivinsky et al., 2004 source

      Not checked in the free run.

    • cites Pena et al., 2008 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Pathogenic SYNGAP1 mutations affect synaptic maturation through cell autonomous mechanisms because no TdTomato-positive neurons were observed outside hippocampus.

    “Importantly, these data also demonstrate that pathogenic SYNGAP1 mutations affect synaptic maturation through cell autonomous mechanisms because we did not observe TdTomato-positive neurons outside the hippocampus.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In early development, many synapse types are morphologically intact and can release glutamate, but most glutamatergic postsynapses on excitatory neurons are not yet functional.

    “While many synapse types are morphologically intact and capable of releasing glutamate, the majority of glutamaterigic post-synapses on excitatory neurons are not yet functional (Ashby and Isaac, 2011; Isaac et al., 1997; Petralia et al., 1999).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ashby and Isaac, 2011

      Not checked in the free run.

    • cites Isaac et al., 1997 source

      Not checked in the free run.

    • cites Petralia et al., 1999 source

      Not checked in the free run.

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

    Interpretationown data

    These results are consistent with signaling deficits previously reported in adult SynGAP mice.

    “These results are consistent with signaling deficits previously reported in adult SynGAP mice (Carlisle et al., 2008; Komiyama et al., 2002).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Carlisle et al., 2008 source

      Not checked in the free run.

    • cites Komiyama et al., 2002 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Southern blot analysis confirmed STOP cassette was appropriately targeted and targeted insertion disrupted expression of full-length SynGAP.

    “Southern blot analysis confirmed that the STOP cassette was appropriately targeted and that this targeted insertion disrupted expression of full-length SynGAP (Figure S6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    This effect was most likely caused by altered SynGAP expression because there was no effect of Cre virus injection in SYNGAP1+/+ mice.

    “This effect was most likely caused by altered SynGAP expression because there was no effect of Cre virus injection in SYNGAP1+/+ mice (Fig. 7C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Inserted LoxP sites were correctly targeted and Cre recombinase expression significantly reduced SynGAP protein levels in SYNGAP1+/fl neurons.

    “We confirmed that the inserted LoxP sites were correctly targeted in this mouse line and that Cre recombinase expression significantly reduced SynGAP protein levels in SYNGAP1+/fl neurons (Figure S5).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A recent report demonstrated that SynGAP can enhance or inhibit dendritic spine synapse function depending on the isoform expressed.

    “Adding to the confusion, a recent report has demonstrated that SynGAP can enhance or inhibit dendritic spine synapse function depending on the particular isoform expressed (McMahon et al., 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McMahon et al., 2012 source

      Not checked in the free run.

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

    Premisecitation

    The role of SynGAP in regulating dendritic spine synapse function has been controversial, with some studies reporting repression and others stimulation.

    “However, the role that SynGAP plays in neurons to regulate dendritic spine synapse function has been controversial because some studies report that SynGAP is a repressor of these synapses (Kim et al., 2005; Rumbaugh et al., 2006; Vazquez et al., 2004), while others report that it stimulates them (Krapivinsky et al., 2004; McMahon et al., 2012).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Kim et al., 2005 source

      Not checked in the free run.

    • cites Rumbaugh et al., 2006 source

      Not checked in the free run.

    • cites Vazquez et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Critical windows of neural plasticity prematurely close or perhaps never open in the neonatal SynGAP heterozygous brain.

    “Due to the pervasive disruption of synapse development and E/I balance in the neonatal SynGAP Het brain, we believe that critical windows of neural plasticity prematurely close or perhaps never open in the first place.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    E/I imbalance is a defining neurophysiological feature of neurodevelopmental disorders.

    “E/I imbalance is a defining neurophysiological feature of neurodevelopmental disorders (Rubenstein and Merzenich, 2003) and elevated excitation is sufficient to disrupt cognition and sociability (Yizhar et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rubenstein and Merzenich, 2003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elevated excitation is sufficient to disrupt cognition and sociability.

    “E/I imbalance is a defining neurophysiological feature of neurodevelopmental disorders (Rubenstein and Merzenich, 2003) and elevated excitation is sufficient to disrupt cognition and sociability (Yizhar et al., 2011).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yizhar et al., 2011 source

      Not checked in the free run.

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

    Study design and conductnone given

    For all studies, the experimenter was blind to genotypes.

    “For all studies, the experimenter was blind to genotypes.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    A network with these irregular features would have altered windows of cortical development, resulting in cognitive dysfunction.

    “A network with these irregular features would be expected to have altered windows of cortical development, resulting in cognitive dysfunction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Local GABAergic networks that counteract excitation develop slowly between PND10-21, contributing to the susceptibility of the neonatal mammalian brain to seizure.

    “However, the local GABAergic networks that counteract excitation develop slowly between PND10-21 (Danglot et al., 2006), contributing to the susceptibility of the neonatal mammalian brain to seizure (Bender et al., 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Danglot et al., 2006 source

      Not checked in the free run.

    • cites Bender et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    This phenomenon is widespread across neocortical dendritic spine synapses and is a primary outcome of pathogenic SYNGAP1 mutations.

    “In addition, we observed this transient change in postsynaptic function at multiple synapses in the hippocampus, indicating that this phenomenon is widespread across neocortical dendritic spine synapses and is a primary outcome of pathogenic SYNGAP1 mutations.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The SynGAP heterozygous mouse model is a valid model of human SYNGAP1 haploinsufficiency and its cognitive symptoms.
41 of 41

  • The paper relies on this without support.

    The mouse SYNGAP1 haploinsufficiency model recapitulates human SYNGAP1 haploinsufficiency and its cognitive/behavioral phenotype.

    “adult SynGAP Heterozygous knockout mice (Hets), which model human SYNGAP1 haploinsufficiency and offer construct validity”
    “In this study, we found that a mouse model of human SYNGAP1 haploinsufficiency had glutamatergic synapses that matured at an accelerated rate during the first few weeks of neonatal development.”

  • The paper relies on this without support.

    The hippocampus is a central mediator of cognition and memory.

    “The hippocampus is a central mediator of cognition and memory, as it receives and integrates information from sensory cortices that is then relayed to associational regions.”

  • The paper relies on this without support.

    Behavioral abnormalities in mice, such as hyperactivity, seizures, and context discrimination deficits, are indicative of neurodevelopmental disorders or intellectual disability.

    “Together, these data link early maturation of dendritic spine synapses and E/I imbalance to the onset of behavioral abnormalities in neonatal SynGAP Het mice.”

  • The paper relies on this without support.

    The SynGAP heterozygous mouse model is a valid model of human SYNGAP1 haploinsufficiency and its cognitive symptoms.

    “In conclusion, we propose that altered E/I balance in early development, which is a major outcome of SYNAGP1 haploinsufficiency, directly contributes to cognitive and behavioral abnormalities observed in this disorder.”

  • The paper relies on this without support.

    The early postnatal period in rodents corresponds to the critical period of human brain development relevant to SYNGAP1 disorder.

    “This critical period of robust synaptogenesis and functional synapse maturation is marked by a steep rise in neural excitability.”

  • The paper relies on this without support.

    Performance in the open field, elevated plus maze, and T-maze in mice reflects cognitive and behavioral abnormalities relevant to human SYNGAP1 haploinsufficiency.

    “Cre+ and Cre− SYNGAP1 LoxP-Stop Hets exhibited increased time in the open arm of the elevated plus maze, increased open field activity levels and the absence of spontaneous alternation in a T-maze.”
6 of 6

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?

  • In the hippocampal dentate gyrus of Syngap1 heterozygous mice, spine maturation and size follow a similar trend to the somatosensory cortex, but dendritic complexity is unaffected.

    “Maturation and size of spines in the hippocampal dentate gyrus of Syngap1 heterozygous mice follow a similar trend to that observed in the somatosensory cortex, although dendritic complexity is not affected in this cortical area [72].”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [72]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Adult spine finding cites juvenile figures

    Minor

    The discussion cites Figures 3A-B for a spine abnormality persisting into adulthood, but the results assign those figures to PND9 and PND14 and identify Figure 3C as the adult finding.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Kim, 2003, The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity, J. Neurosci., 23, 1119, 10.1523/jneurosci.23-04-01119.2003 · DOI · Paper page
  2. Guo, X., Hamilton, P.J., Reish, N.J., Sweatt, J.D., Miller, C.A., and Rumbaugh, G. (2009). Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of Schizophrenia. Neuropsychopharmacology 34, 1659–1672. · DOI · Paper page
  3. Majewska, A., and Sur, M. (2003). Motility of dendritic spines in visual cortex in vivo: changes during the critical period and effects of visual deprivation. Proc. Natl. Acad. Sci. USA 100, 16024–16029. · DOI

Cited by

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Authors
Clement, J. P., Aceti, M., Creson, T. K., Ozkan, E. D., Shi, Y., Reish, N. J., Almonte, A. G., Miller, B. H., Wiltgen, B. J., Miller, C. A., Xu, X., & Rumbaugh, G.
Affiliations
  • Scripps Research Institute (US)
  • University of California, Irvine (US)
  • University of Alabama at Birmingham (US)
  • University of Virginia (US)
Corresponding author
Rumbaugh, Gavin
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2012-11
Volume
151
Issue
4
Pages
709-723
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2012.08.045
PMC
PMC3500766
OpenAlex
W2114350859
Semantic Scholar
b083bfa2498e6e12354f53950c7d5296fdb7600a
Cited by
385
References
67
Citations by year
2026: 20 · 2025: 31 · 2024: 40 · 2023: 26 · 2022: 32 · 2021: 30 · 2020: 35 · 2019: 22 · 2018: 33 · 2017: 24 · 2016: 28 · 2015: 23 · 2014: 21 · 2013: 18 · 2012: 2
FWCI
12.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Mental Health (R01MH096847)
  • National Institute on Drug Abuse (R00DA023700, DA023700-04S1, K99DA023700)
  • National Institute of Neurological Disorders and Stroke (R01NS064079)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD060672)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
SYNGAP1, intellectual disability, autism spectrum disorder, dendritic spine maturation, synaptic development, neuronal excitability, hippocampus, cognitive development, postnatal development, mouse model, behavioral abnormalities
MeSH terms
Animals, Cognition Disorders, Disease Models, Animal, Female, Hippocampus, Humans, Male, Memory, Mice, Inbred C57BL, Nerve Net, Synapses, Mice, Knockout, ras GTPase-Activating Proteins, Dendritic Spines, Mice, Haploinsufficiency

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