Cited by 129Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchGenomic variations and chromosomal abnormalities

Syngap1 Haploinsufficiency Damages a Postnatal Critical Period of Pyramidal Cell Structural Maturation Linked to Cortical Circuit Assembly

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Aceti, Massimiliano, Creson, Thomas K., Vaissiere, Thomas, Rojas, Camilo, Huang, Wen-Chin, Wang, Ya-Xian, Petralia, Ronald S., Page, Damon T. +2 more·2015·Biological Psychiatry

Abstract

Background Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders.Methods A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development.Results Syngap1 mutations broadly disrupted a developmentally sensitive period that corresponded to the period of heightened postnatal cortical synaptogenesis. Pathogenic Syngap1 mutations caused a coordinated acceleration of dendrite elongation and spine morphogenesis and pruning of these structures in neonatal cortical pyramidal neurons. These mutations also prevented a form of developmental structural plasticity associated with experience-dependent reorganization of brain circuits. Consistent with these findings, Syngap1 mutant mice displayed an altered pattern of long-distance synaptic inputs into a cortical area important for cognition. Interestingly, the ability to genetically improve the behavioral endophenotype of Syngap1 mice decreased slowly over postnatal development and mapped onto the developmental period of coordinated dendritic insults.Conclusions Pathogenic Syngap1 mutations have a profound impact on the dynamics and structural integrity of pyramidal cell postsynaptic structures known to guide the de novo wiring of nascent cortical circuits. These findings support the idea that disrupted critical periods of dendritic growth and spine plasticity may be a common pathologic process in developmental brain disorders.

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Crossref · 10.1016/j.biopsych.2014.08.001

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  • At P21, dendritic spine head size was significantly smaller in Srgap2 heterozygous CPNs and significantly larger in Syngap1 heterozygous CPNs compared with wild-type layer 2/3 CPNs.

    “As reported previously,24,29,39 morphological analyses at P21 revealed that dendritic spine head size was significantly smaller in Srgap2 heterozygous CPNs and significantly larger in Syngap1 heterozygous CPNs compared with wild-type layer 2/3 CPNs (Figures 6B–6D and S10D).”

    From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [39]

    The Results (page not provided) report altered spine size in Syngap1 heterozygous layer 2/3 neurons at PND14 and enlarged spines in adult layer 2/3 neurons. They also report larger newly formed spines at PND21–23, but those were in layer 5 neurons. The cited paper therefore supports the direction of the Syngap1 finding, not the specific P21 layer 2/3 spine-head comparison; the Srgap2 finding is not attributed to this source alone. (LLM, conf=0.83)

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  • Previous work has pointed to increased synapse formation in Syngap1+/− juvenile mutant mice, suggestive of accelerated synaptic development.

    “Previous work has pointed to increased synapse formation in Syngap1+/− juvenile mutant mice, suggestive of accelerated synaptic development.39”
  • At P21, dendritic spine head size was smaller and dendritic spine density higher in SRGAP2C gain-of-function CPNs.

    “As reported previously,24,29,39 analysis at P21 revealed that dendritic spine head size was smaller and dendritic spine density higher in SRGAP2C gain-of-function CPNs24,29 (Figures 6B–6D and S10B–S10D).”

    From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [39]

    The Results passages describe Syngap1-haploinsufficient mice, not SRGAP2C gain-of-function cortical projection neurons. They report enlarged newly formed spines at PND21–23 and altered spine density during development, but do not address the claimed P21 combination of smaller spine heads and higher density in SRGAP2C gain-of-function cells (searched: SRGAP2C gain-of-function, PND21 spine size and density). (LLM, conf=0.76)

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  • In mice mimicking the Syngap1 deficit, layer V pyramidal neurons of the somatosensory cortex show precocious dendritic arborization, early spine formation and premature pruning, and enlarged spines during a critical developmental period compared with wild-type mice.

    “Studies using genetically modified mice that mimic the Syngap1 deficit have revealed precocious dendritic arborization, early formation and premature pruning of dendritic spines as well as enlarged dendritic spines in layer V pyramidal neurons of the somatosensory cortex during a critical period of development, compared to WT mice [2].”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [2]

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Research works printed but not linked: 1

  1. [38]Hamdan FF Gauthier J Spiegelman D Noreau A Yang Y Pellerin S 2009 Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation The New England journal of medicine 360 599 605 19196676 PMC2925262

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Authors
Aceti, M., Creson, T. K., Vaissiere, T., Rojas, C., Huang, W.-C., Wang, Y.-X., Petralia, R. S., Page, D. T., Miller, C. A., & Rumbaugh, G.
Affiliations
  • Scripps Research Institute (US)
  • National Institutes of Health (US)
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2015-05
Volume
77
Issue
9
Pages
805-815
ISSN
0006-3223 (ISSN-L)
OpenAlex
W2007942788
Cited by
129
References
44
Citations by year
2026: 11 · 2025: 12 · 2024: 13 · 2023: 14 · 2022: 14 · 2021: 14 · 2020: 12 · 2019: 11 · 2018: 10 · 2017: 11 · 2016: 6 · 2015: 1
FWCI
3.93
Type
journal article
Language
en
Open access
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • The National Institute for Neurological Disorders and Stroke (R01NS064079)
  • The National Institute for Mental Health (R01MH096847)
  • National Institute for Drug Abuse (R01 DA034116, R03 DA033499)
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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
SYNGAP1, haploinsufficiency, dendritic spine maturation, cortical pyramidal neurons, synaptogenesis, dendrite elongation, synaptic pruning, experience-dependent plasticity, intellectual disability, epilepsy, autism spectrum disorder, schizophrenia, genetic rescue, mouse model
MeSH terms
Animals, Animals, Newborn, Cerebral Cortex, Conditioning, Psychological, Exploratory Behavior, Fear, Hippocampus, Mice, Transgenic, Neural Pathways, Sensory Deprivation, Vibrissae, Pyramidal Cells, Maze Learning, ras GTPase-Activating Proteins, Dendritic Spines, Haploinsufficiency, Endophenotypes

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