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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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“Dendritic arborization is known to occur early in development, with arbors reaching near adult size by P21 in mice, and subsequent changes acting primarily to refine circuitry (64, 65).”
Protein synthesis as a modifiable target for autism‐related dendritic spine pathophysiologies
Lu, M., & Hsueh, Y. (2021) · FEBS Journal · doi:10.1111/febs.15733 · Cited by 15
Khlaifia, A., Jadhav, V., Danik, M., Badra, T., Berryer, M. H., Dionne‐Laporte, A., Chattopadhyaya, B., Cristo, G. D., Lacaille, J., & Michaud, J. L. (2023) · eNeuro · doi:10.1523/eneuro.0475-22.2023 · Cited by 13
“…interneurons Given that AMPAR-mediated synaptic transmission is regulated by SYNGAP1 in excitatory neurons (Clement et al., 2012; Wang et al., 2013; Aceti et al., 2015; Araki et al., 2015; Walkup et al., 2016), we explored whether Syngap1 decrease in MGE-derived interneurons affects AMPARmediated…”
BackgroundInfluentialUnderstanding the role of AMPA receptors in autism: insights from circuit and synapse dysfunction
Jiménez-Gómez, A., Nguyen, M. X., & Gill, J. S. (2024) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2024.1304300 · Cited by 14
Fenton, T. A., Haouchine, O. Y., Hallam, E. B., Smith, E. M., Jackson, K. C., Rahbarian, D., Canales, C. P., Adhikari, A., Nord, A. S., Ben‐Shalom, R., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03077-6 · Cited by 13
Fung, C. M. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1092357 · Cited by 14
“Dysregulation of the timing of the critical period perturbs the excitatory/inhibitory balance and is postulated to contribute to developmental disorders and psychopathology in at-risk individuals (Aceti et al., 2015; Meredith, 2015).”
BackgroundHaetzel, L. M., Iafrati, J., Cording, K. R., Farhan, M., Noveir, S. D., Rumbaugh, G., & Bateup, H. S. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.1264-23.2024 · Cited by 12
Self-citationSyngap1 promotes cognitive function through regulation of cortical sensorimotor dynamics
Vaissière, T., Michaelson, S. D., Creson, T. K., Goins, J., Fürth, D., Balázsfi, D., Rojas, C., Golovin, R. M., Meletis, K., Miller, C. A., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56125-0 · Cited by 13
“Third, within S1, Syngap1 regulates dendritic morphogenesis in deep neurons 74 and developmental synaptic connectivity of feed-forward excitation in upper lamina neurons 23 , which could lead to circuit connectivity alterations capable of in fl uencing neuronaldynamicswithinthiscorticalarea.”
InfluentialSelf-citationEpigenetic modulation rescues neurodevelopmental deficits in Syngap1+/− mice
Singh, A. K., Joshi, I., Reddy, N. M. N., Purushotham, S. S., Eswaramoorthy, M., Vasudevan, M., Banerjee, S., Clement, J. P., & Kundu, T. K. (2025) · Aging Cell · doi:10.1111/acel.14408 · Cited by 13
Megagiannis, P., Suresh, R., Rouleau, G. A., & Zhou, Y. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114562 · Cited by 12
Animal models of autism: a perspective from autophagy mechanisms
Dana, H., Tahtasakal, R., & Şener, E. F. (2020) · Journal of Translational Genetics and Genomics · doi:10.20517/jtgg.2020.25 · Cited by 12
“The emerging risk genes are as follows: CHD8, SCN2A, SYNGAP1, DSCAM, and TBR1[65-69].”
BackgroundHuman synaptic neoteny requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibitionPreprint
Libé‐Philippot, B., Iwata, R., Recupero, A. J., Wierda, K. D. B., Ditkowska, M., Gaspariunaite, V., Vermaercke, B., Pezé-Heidsieck, E., Remans, D., Charrier, C., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.03.01.530630 · Cited by 12
Interactions between Ras and Rap signaling pathways during neurodevelopment in health and disease
Cherra, S. J., & Lamb, R. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1352731 · Cited by 11
Macías, M., & Urwyler, O. (2021) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.755686 · Cited by 11
“By contrast, the “division of labor” between isoforms is different in another major neuronal SynGAP function, namely the control of developmental dendrite morphogenesis andmaturation (Aceti et al., 2015; Araki et al., 2020).”
BackgroundPierre, M. S., Rastogi, N., Brown, A., Parmar, P., Lechner, C., Fung, C. M., & Chavez‐Valdez, R. (2021) · Developmental Neuroscience · doi:10.1159/000521611 · Cited by 11
Brimble, E., Lee‐Messer, C., Nagy, P. L., Propst, J., & Ruzhnikov, M. R. Z. (2018) · Molecular Syndromology · doi:10.1159/000492706 · Cited by 10
“, 2006], and disruption of cortical pyramidal neuron development with diminished dendritic spine dynamics and plasticity [Aceti et al., 2015].”
BackgroundRigter, P. M. F., Wallaard, I., Jolfaei, M. A., Kingma, J., Post, L. C., Elgersma, M., Elgersma, Y., & van Woerden, G. M. (2022) · iScience · doi:10.1016/j.isci.2022.105303 · Cited by 10
“Current literature shows that the answer to this question depends strongly on the gene involved in the NDD and the behaviour tested (Aceti et al., 2015; Clement et al., 2012; Guy et al., 2007; Lang et al., 2014; Mei et al., 2016; Mielnik et al., 2020; Silva-Santos et al., 2015).”
BackgroundInfluentialWang, Y., Lv, Y., Li, Z., Gao, M., Yang, X., Li, Y., Shi, J., Gao, Z., Liu, Y., & Gai, Z. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.957915 · Cited by 9
“Aberrant alterations greatly affect neural development, including increased excitability, excitation/inhibition imbalance, and loss of experiencedependent plasticity, which are responsible for cognition, learning, memory, and motor defects (Aceti et al., 2015; Uzunova et al., 2016; Zhang Y et al., 2020; Ni and Li, 202…”
BackgroundSelf-citationJadhav, V., Carreño-Muñoz, M. I., Chehrazi, P., Michaud, J. L., Chattopadhyaya, B., & Cristo, G. D. (2024) · Journal of Neuroscience · doi:10.1523/jneurosci.0946-24.2024 · Cited by 8
Yang, X. Y., Stanley, R., Ross, A. P., Robitaille, A. M., Gray, J. A., & Cheyette, B. N. R. (2017) · Cerebral Cortex · doi:10.1093/cercor/bhx333 · Cited by 9
“2014; Spence and Soderling 2015; Woolfrey and Srivastava 2016; Hedrick and Yasuda 2017), and given the fundamental importance of these processes to complex behavior and neuropsychiatry (Oh et al. 2010; Durand et al. 2012; Pavlowsky et al. 2012; Konopaske et al. 2014; Aceti et al. 2015), we conducted the present study…”
BackgroundSyngap1 Regulates Cortical Circuit Assembly by Controlling Membrane ExcitabilityPreprint
Arora, V., Michaelson, S. D., Aceti, M., Kilinic, M., Miller, C. A., & Rumbaugh, G. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.12.06.519295 · Cited by 7
“As previously described (Aceti et al., 2015), ten to fifteen dendritic segments of SSC L2/3 neurons (20–90 μm in length) at P14 mice were collected and considered for analysis.”
BackgroundMethodInfluentialSelf-citationActivity-Dependent Stabilization of Nascent Dendritic Spines Requires Nonenzymatic CaMKIIα Function
Claiborne, N., Anisimova, M., & Zito, K. (2023) · Journal of Neuroscience · doi:10.1523/jneurosci.1393-22.2023 · Cited by 8
Noh, Y. W., Yook, C., Kang, J., Lee, S., Kim, Y., Yang, E., Kim, H., & Kim, E. (2022) · Communications Biology · doi:10.1038/s42003-022-03813-y · Cited by 8
The autism-associated gene SYNGAP1 regulates human cortical neurogenesisPreprint
Birtele, M., Dosso, A. D., Xu, T., Nguyen, T. N., Wilkinson, B., Hosseini, N., Nguyen, S. C., Urenda, J., Knight, G. T., Rojas, C., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.10.491244 · Cited by 7
Self-citationAivazidis, A., Memi, F., Rademaker, K., Koko, M., Roberts, K., Trinh, A. L., Petryszak, R., Kleshchevnikov, V., Tuck, E. J., Lisgo, S., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.05.685843 · Cited by 6
Harrison, A., Magielski, J. H., McSalley, I., Ganesan, S., Prentice, A. J., Cunningham, K. G., Pierce, S. R., Boland, M. J., Prosser, B. L., Helbig, I., et al. (2025) · Epilepsia · doi:10.1111/epi.18469 · Cited by 5
Samanta, D. (2026) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2026.111098 · Cited by 5
Deciphering the role of CAPZA2 in neurodevelopmental disorders: insights from mouse models
Guo, M., Liu, L., Mao, X. O., Xiao, M., He, X., Pan, X., Chen, Y., Yi, W., Li, Q., Piao, X., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-08385-1 · Cited by 5
Hafenbreidel, M., Pandey, S., Briggs, S., Arza, M., Bonthu, S., Fisher, C., Tiller, A., Hall, A. B., Reed, S., Mayorga, N., et al. (2023) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2023.107865 · Cited by 5
Self-citationBehavioural and neurodevelopmental characteristics of SYNGAP1
Bednarczuk, N. F., Housby, H., Lee, I., Skuse, D., & Wolstencroft, J. (2024) · Journal of Neurodevelopmental Disorders · doi:10.1186/s11689-024-09563-8 · Cited by 9
“Non-synaptic functions have also been linked to SynGAP, including axonal outgrowth and neuronal migration [5, 6].”
BackgroundInfluentialHyperexcitability and translational phenotypes in a preclinical model of SYNGAP1 mutationsPreprint
Fenton, T. A., Haouchine, O. Y., Hallam, E. L., Smith, E. M., Jackson, K. C., Rahbarian, D., Canales, C. P., Adhikari, A., Nord, A. S., Ben‐Shalom, R., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.24.550093 · Cited by 4
“Earlier work with SynGAP1 illustrated hardwiring of neural circuitry that manifest as lifelong impairments.(65,66) Nonetheless, crucial to this work, re-expression of Syngap1 by genetic reversal exhibits a complete”
BackgroundLevman, J. E. D. (2025) · Biology · doi:10.3390/biology14121651 · Cited by 3
“Genetic haploinsufficiency (common in autism spectrum disorder) associated mutations caused a coordinated acceleration of pruning in a mouse model [131], indicating that there may be associations between autism spectrum disorder and tissue removal irregularities.”
Francavilla, R., Chattopadhyaya, B., Kamda, J. L. D., Jadhav, V., Kourrich, S., Michaud, J. L., & Cristo, G. D. (2024) · eLife · doi:10.7554/elife.97100.4 · Cited by 5
Stamenković, V., Harsh, F. M., Kniffen, B., Rumbaugh, G., & Smith, S. E. P. (2026) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2026.101614 · Cited by 3
“Finally, our approach was limited to the biochemical effects of rescue, and did not examine known deficits in SynGAP mice such as synaptodendritic structure (21) or behavior (22) that have been previously documented to be resistant to rescue.”
InfluentialSelf-citationQvist, J. S., Scherma, M., Jayaram‐Lindström, N., Fratta, W., Kandel, D. B., Kandel, E. R., Fadda, P., & Melas, P. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010698 · Cited by 4
“Moreover, a previous report that utilized a SYNGAP1 haploinsufficiency mouse model, found evidence for hyperconnectivity in the amygdala of SYNGAP1 mutant mice [39], further supporting a key role for SYNGAP1 in this brain region.”
ResultLomash, R. M., Petralia, R. S., Holtzclaw, L. A., Tsuda, M. C., Wang, Y., Badger, J. D., Cameron, H. A., Youle, R. J., & Roche, K. W. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.007245 · Cited by 3
“1 M phosphate buffer, followed by fixation in 4% PFA plus 2% glutaraldehyde in the same buffer at RT overnight (52).”
MethodSelf-citationSYNGAP1 deficiency disrupts neoteny in human cortical neurons in vivoPreprint
Vermaercke, B., Iwata, R., Weirda, K., Boubakar, L., Rodríguez, P., Ditkowska, M., Bonin, V., & Vanderhaeghen, P. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.14.524054 · Cited by 3
Genetic and Pharmacological Reversibility of Phenotypes in Mouse Models of Autism Spectrum Disorder
Schroeder, J. C., Deliu, E., Novarino, G., & Schmeißer, M. J. (2017) · Advances in anatomy, embryology and cell biology · doi:10.1007/978-3-319-52498-6_10 · Cited by 2
Critical periods and neurodevelopmental brain disorders
Meredith, R. M. (2016) · Wiley eBooks · doi:10.1002/9781118931684.ch4 · Cited by 2
Llamosas, N., Arora, V., Vij, R., Kılınç, M., Bijoch, Ł., Rojas, C., Reich, A. M., Sridharan, B., Willems, E., Piper, D. R., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.01.127613 · Cited by 2
Self-citationLiu, Y., Lang, B., Smith, R. C., Wang, G., Wang, J., Liu, Y., Jin, H., Lyu, H., Davis, J. M., Guidotti, A. R., et al. (2021) · SSRN Electronic Journal · doi:10.1101/2021.02.07.430160 · Cited by 2
Katsanevaki, D., Dupuy, N., Booker, S. A., Wright, D., Kenny, A., Chen, Z., Kudryashova, N., Howitt, P., Stanfield, A. C., Kind, P. C., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.09.647923 · Cited by 2
Jiang, J. P., Rust, R., Flores, I., Feng, Y., Nouri, P., Clementel, V. A., Arya, A., Basirattalab, A., Yang, I. Y., Manousopoulou, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.24.707848 · Cited by 3
“SYNGAP1 function has largely been studied within the context of mature rodent excitatory synapses from glutamatergic neurons 12-18 .”
Dual diagnosis causing severe phenotype in a patient with Angelman syndrome
Kanani, F., Mordekar, S., Parker, M. J., & Balasubramanian, M. (2019) · Clinical Dysmorphology · doi:10.1097/mcd.0000000000000280 · Cited by 1
“Recent studies have shown truncating mutations in SYNGAP1 to be the cause of intellectual disability, indicating that the phenotype is likely secondary to haploinsufficiency of the gene and its protein product (Berryer et al., 2013; Aceti et al., 2015).”
BackgroundPreclinical models for autism spectrum disorder: past, present, and future
Dwivedi, S., Rajput, P., Akhtar, A., Goli, S. H., & Dusane, A. (2025) · Neuroscience · doi:10.1016/j.neuroscience.2025.10.063 · Cited by 1
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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