The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Syngap1 Haploinsufficiency Damages a Postnatal Critical Period of Pyramidal Cell Structural Maturation Linked to Cortical Circuit Assembly
Open accessAbstract
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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“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]
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“Previous work has pointed to increased synapse formation in Syngap1+/− juvenile mutant mice, suggestive of accelerated synaptic development.39”
From Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition (2024) · cites this paper as [39]
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“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]
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“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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Citations
Cites
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Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509 · cited 1×
“To probe for possible signaling abnormalities underlying accelerated neuronal growth in hets, we examined levels of phosphorylated S6 (p-S6), a marker of mTORC1-mediated cellular growth and protein synthesis (30, 31).”
BackgroundSporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165
De novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084
Functional impact of global rare copy number variation in autism spectrum disorders
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Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex
Trachtenberg, J. T., Chen, B. E., Knott, G. W., Feng, G., Sanes, J. R., Welker, E., & Svoboda, K. (2002) · Nature · doi:10.1038/nature01273 · Cited by 1,927 · cited 3×
“Indeed, the dynamic formation and elimination of dendritic spines reflects functional reorganization of neural circuits (33, 34).”
BackgroundMethodPatterns and rates of exonic de novo mutations in autism spectrum disorders
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., et al. (2012) · Nature · doi:10.1038/nature11011 · Cited by 1,734
De novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · cited 4×
“Background—Genetic haploinsufficiency of Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability (ID), epilepsy, schizophrenia (SCZ), and autism spectrum (ASD) disorder.”
BackgroundInfluentialDiagnostic exome sequencing in persons with severe intellectual disability
de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1206524 · Cited by 1,546 · cited 1×
“Current estimates indicate that pathogenic Syngap1 mutations account for 2–8% of sporadic ID cases (2, 3, 14, 17, 19) and up to 1% of EE cases (1), suggesting that there are tens-of-thousands of undocumented individuals carrying these mutations.”
BackgroundDendritic spine pathology in neuropsychiatric disorders
Penzes, P., Cahill, M. E., Jones, K. A., VanLeeuwen, J.-E., & Woolfrey, K. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2741 · Cited by 1,523 · cited 2×
“Spine pruning is believed to be an essential developmental process that reflects the refinement of cortical circuits and improved mental ability (21, 43, 44).”
BackgroundDe Novo Gene Disruptions in Children on the Autistic Spectrum
Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y.-H., Narzisi, G., Leotta, A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.04.009 · Cited by 1,446
Cited by
Sorted by citations
Items 101–128 of 128
Imaging Synapse Formation and Remodeling In Vitro and In Vivo
Okabe, S. (2019) · Springer eBooks · doi:10.1007/978-981-13-7908-6_19 · Cited by 2
GABAergic signaling promotes early-life seizures in epileptic SYNGAP1 +/- micePreprint
Sullivan, B. J., Kipnis, P. A., Ammanuel, S. G., & Kadam, S. D. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.11.14.381749 · Cited by 1
Verma, V., Kumar, M. V., Sharma, K., Rajaram, S., Muddashetty, R. S., Manjithaya, R. R., Behnisch, T., & Clement, J. P. (2021) · Research Square · doi:10.21203/rs.3.rs-682039/v1 · Cited by 1
Hafenbreidel, M., Briggs, S., Arza, M., Bonthu, S., Fisher, C., Tiller, A., Hall, A. B., Reed, S., Mayorga, N., Lin, L., et al. (2023) · bioRxiv · doi:10.1101/2023.05.22.541732 · Cited by 1
Self-citationHyperexcitability and translational phenotypes in a preclinical model of SYNGAP1 mutationsPreprint
Silverman, J. L., Fenton, T., Haouchine, O. Y., Hallam, E., Smith, E., Jackson, K. C., Rahbarian, D., Canales, C. P., Adhikari, A., Nord, A. S., et al. (2023) · Research Square · doi:10.21203/rs.3.rs-3246655/v1 · Cited by 1
Behavioural and neurodevelopmental characteristics of SYNGAP1Preprint
Bednarczuk, N. F., Housby, H., Lee, I., Skuse, D., & Wolstencroft, J. (2023) · Research Square · doi:10.21203/rs.3.rs-3722732/v1 · Cited by 1
Singh, A. K., Joshi, I., Reddy, N. M. N., Purushotham, S. S., Eswaramoorthy, M., Vasudevan, M., Banerjee, S., Clement, J. P., & Kundu, T. K. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.03.574003 · Cited by 1
“Previously, it has been reported that, upon whisker deprivation during critical developmental period, Syngap1 +/- mice had fewer filopodia in the somatosensory cortex as compared to WT animals ( 20 ).”
ResultFrancavilla, R., Chattopadhyaya, B., Kamda, J. L. D., Jadhav, V., Kourrich, S., Michaud, J. L., & Cristo, G. D. (2024) · eLife · doi:10.7554/elife.97100.1 · Cited by 1
Francavilla, R., Chattopadhyaya, B., Kamda, J. L. D., Jadhav, V., Kourrich, S., Michaud, J. L., & Cristo, G. D. (2024) · eLife · doi:10.7554/elife.97100.2 · Cited by 1
James, L. M., Friar, C. A., Liang, S., Gao, E. B., Burette, A. C., & Philpot, B. D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.23.696277 · Cited by 2
Kılınç, M., Creson, T. K., Rojas, C., Maity, S., Le, A. A., Lauterborn, J. C., Wilkinson, B., Hartel, N. G., Graham, N. A., Reich, A. M., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.01.18.911487
“However, additional research is required to determine how re-expression of individual SynGAP C-terminal isoforms in animal models impact reversible phenotypes associated with the human disorder (Aceti et al., 2015; Clement et al., 2012; Creson et al., 2019; Ozkan et al., 2014).”
BackgroundSelf-citationLlamosas, N., Vaissière, T., Rojas, C., Michaelson, S. D., Miller, C. A., & Rumbaugh, G. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.04.14.041038
Self-citationLai, T. K. Y. (2019) · TSpace (University of Toronto)
SYNGAP1 and Its Related Epileptic Syndromes
Garozzo, M. T., Caruso, D., Mendola, F., Nora, A. D., Romano, K., Leonardi, R., Falsaperla, R., Zanghì, A., & Praticò, A. D. (2021) · Journal of Pediatric Neurology · doi:10.1055/s-0041-1727144
Smith, S. E. (2020) · The Research Repository @ WVU (West Virginia University) · doi:10.33915/etd.7976
Human-mouse chimeric Fragile X syndrome model reveals FMR1-dependent neuronal phenotypesPreprint
Krzisch, M., Wu, H., Yuan, B., Whitfield, T. W., Liu, X. S., Fu, D., Garrett-Engele, C. M., Chang, A. N., Warren, S. T., Cacace, A. M., et al. (2020) · Research Square · doi:10.21203/rs.3.rs-83372/v1
Rigter, P. M. F., Wallaard, I., Jolfaei, M. A., Kingma, J., Post, L. C., Elgersma, M., Elgersma, Y., & van Woerden, G. M. (2022) · SSRN Electronic Journal · doi:10.2139/ssrn.4143785
Jacob, M. H., Alexander, J., Jin, S., & Feig, L. A. (2023) · Research Square · doi:10.21203/rs.3.rs-2334720/v1
Francavilla, R., Chattopadhyaya, B., Kamda, J. L. D., Jadhav, V., Kourrich, S., Michaud, J. L., & Cristo, G. D. (2025) · eLife · doi:10.7554/elife.97100.3
James, L. M., Friar, C. A., Liang, S., Gao, E. B., Burette, A. C., & Philpot, B. D. (2026) · eLife · doi:10.7554/elife.110213
James, L. M., Friar, C. A., Liang, S., Gao, E. B., Burette, A. C., & Philpot, B. D. (2026) · eLife · doi:10.7554/elife.110213.1
Local translational repression and retention of SynGAP1 during synaptic plasticityPreprint
Livingstone, R. W., & Donlin-Asp, P. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.29.719691
The Synaptic Clock: SynGAP1 as a Molecular Timer of Postsynaptic Density Consolidation
Cao, Z., Jia, Y., Zhang, Z., Xue, H., Yu, H. D., Li, X., & Luo, P. (2026) · Biomolecules · doi:10.3390/biom16060876
“Early postnatal genetic rescue robustly normalizes structural/spine deficits [13–15, 57, Are upstream protein-restoring therapies (e.g., ASOs) fundamentally superior to downstream catalytic modulation across all developmental phases?”
Félix, A. J., Brown, B. L., Marotta, N., Gessner, M. J., Houserova, M., Huerta-Ocampo, I., Wilson, T., Randell, R., Dawicki-McKenna, J. M., Reinhardt, D., et al. (2026) · Molecular Psychiatry · doi:10.1038/s41380-026-03698-x · Cited by 6
Li, Y., Liao, Y., Zhang, S., Xu, C., Lan, R., Zhao, P., Liu, R., Song, Y., & Zhang, X. (2026) · Frontiers in Synaptic Neuroscience · doi:10.3389/fnsyn.2026.1923815
Pacheva, I. H. (2026) · Genes · doi:10.3390/genes17101308
“…of excitatory-synapse maturation and critical-period plasticity is linked to both neurodevelopmental dysfunction and seizure susceptibility [56–58], whereas in SHANK3 - and STXBP1 -related disorders the evidence for a single shared mechanism specifically linking ASD and epilepsy is less…”
Desprez, F., & Ung, D. C. (2026) · Journal of Neural Transmission · doi:10.1007/s00702-026-03315-9
Metadata
- 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)
- ORCID
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 77
- Issue
- 9
- Pages
- 805-815
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4326604
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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