Dissociation of SYNGAP1 Enzymatic and Structural Roles: Intrinsic Excitability and Seizure Susceptibility

Overview

Journal bioRxiv

Date 2025 Jan 27

PMID 39868300

Authors

Julia Brill

Blaise Clarke

Ingie Hong

Richard L Huganir

Affiliations

Soon will be listed here.

Abstract

SYNGAP1 is a key Ras-GAP protein enriched at excitatory synapses, with mutations causing intellectual disability and epilepsy in humans. Recent studies have revealed that in addition to its role as a negative regulator of G-protein signaling through its GAP enzymatic activity, SYNGAP1 plays an important structural role through its interaction with post-synaptic density proteins. Here, we reveal that intrinsic excitability deficits and seizure phenotypes in heterozygous Syngap1 knockout (KO) mice are differentially dependent on Syngap1 GAP activity. Cortical excitatory neurons in heterozygous KO mice displayed reduced intrinsic excitability, including lower input resistance, and increased rheobase, a phenotype recapitulated in GAP-deficient Syngap1 mutants. However, seizure severity and susceptibility to pentylenetetrazol (PTZ)-induced seizures were significantly elevated in heterozygous KO mice but unaffected in GAP-deficient mutants, implicating the structural rather than enzymatic role of Syngap1 in seizure regulation. These findings highlight the complex interplay between SYNGAP1 structural and catalytic functions in neuronal physiology and disease.

References

Bayliss D, Sirois J, Talley E . The TASK family: two-pore domain background K+ channels. Mol Interv. 2004; 3(4):205-19. DOI: 10.1124/mi.3.4.205. View

Ozkan E, Creson T, Kramar E, Rojas C, Seese R, Babyan A . Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron. 2014; 82(6):1317-33. PMC: 4104574. DOI: 10.1016/j.neuron.2014.05.015. View

Fenton T, Haouchine O, Hallam E, Smith E, Jackson K, Rahbarian D . Hyperexcitability and translational phenotypes in a preclinical mouse model of SYNGAP1-related intellectual disability. Transl Psychiatry. 2024; 14(1):405. PMC: 11447000. DOI: 10.1038/s41398-024-03077-6. View

Kim J, Liao D, Lau L, Huganir R . SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. Neuron. 1998; 20(4):683-91. DOI: 10.1016/s0896-6273(00)81008-9. View

Gou G, Roca-Fernandez A, Kilinc M, Serrano E, Reig-Viader R, Araki Y . SynGAP splice variants display heterogeneous spatio-temporal expression and subcellular distribution in the developing mammalian brain. J Neurochem. 2020; 154(6):618-634. PMC: 7754318. DOI: 10.1111/jnc.14988. View

Araki Y, Hong I, Gamache T, Ju S, Collado-Torres L, Shin J . SynGAP isoforms differentially regulate synaptic plasticity and dendritic development. Elife. 2020; 9. PMC: 7314543. DOI: 10.7554/eLife.56273. View

Zeng M, Shang Y, Araki Y, Guo T, Huganir R, Zhang M . Phase Transition in Postsynaptic Densities Underlies Formation of Synaptic Complexes and Synaptic Plasticity. Cell. 2016; 166(5):1163-1175.e12. PMC: 5564291. DOI: 10.1016/j.cell.2016.07.008. View

Tomoda T, Kim J, Zhan C, Hatten M . Role of Unc51.1 and its binding partners in CNS axon outgrowth. Genes Dev. 2004; 18(5):541-58. PMC: 374236. DOI: 10.1101/gad.1151204. View

Ciganok-Huckels N, Jehasse K, Kricsfalussy-Hrabar L, Ritter M, Ruland T, Kampa B . Postnatal development of electrophysiological and morphological properties in layer 2/3 and layer 5 pyramidal neurons in the mouse primary visual cortex. Cereb Cortex. 2022; 33(10):5875-5884. PMC: 10183751. DOI: 10.1093/cercor/bhac467. View

10.

Araki Y, Gerber E, Rajkovich K, Hong I, Johnson R, Lee H . Mouse models of -related intellectual disability. Proc Natl Acad Sci U S A. 2023; 120(37):e2308891120. PMC: 10500186. DOI: 10.1073/pnas.2308891120. View

11.

Oswald A, Reyes A . Maturation of intrinsic and synaptic properties of layer 2/3 pyramidal neurons in mouse auditory cortex. J Neurophysiol. 2008; 99(6):2998-3008. PMC: 3056441. DOI: 10.1152/jn.01160.2007. View

12.

Araki Y, Zeng M, Zhang M, Huganir R . Rapid dispersion of SynGAP from synaptic spines triggers AMPA receptor insertion and spine enlargement during LTP. Neuron. 2015; 85(1):173-189. PMC: 4428669. DOI: 10.1016/j.neuron.2014.12.023. View

13.

Clement J, Aceti M, Creson T, Ozkan E, Shi Y, Reish N . Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses. Cell. 2012; 151(4):709-723. PMC: 3500766. DOI: 10.1016/j.cell.2012.08.045. View

14.

David F, Carcak N, Furdan S, Onat F, Gould T, Meszaros A . Suppression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function in Thalamocortical Neurons Prevents Genetically Determined and Pharmacologically Induced Absence Seizures. J Neurosci. 2018; 38(30):6615-6627. PMC: 6067077. DOI: 10.1523/JNEUROSCI.0896-17.2018. View

15.

Van Erum J, Van Dam D, De Deyn P . PTZ-induced seizures in mice require a revised Racine scale. Epilepsy Behav. 2019; 95:51-55. DOI: 10.1016/j.yebeh.2019.02.029. View

16.

Katsanevaki D, Till S, Buller-Peralta I, Nawaz M, Louros S, Kapgal V . Key roles of C2/GAP domains in SYNGAP1-related pathophysiology. Cell Rep. 2024; 43(9):114733. DOI: 10.1016/j.celrep.2024.114733. View

17.

Zhu J, Qin Y, Zhao M, Van Aelst L, Malinow R . Ras and Rap control AMPA receptor trafficking during synaptic plasticity. Cell. 2002; 110(4):443-55. DOI: 10.1016/s0092-8674(02)00897-8. View

18.

Vazquez L, Chen H, Sokolova I, Knuesel I, Kennedy M . SynGAP regulates spine formation. J Neurosci. 2004; 24(40):8862-72. PMC: 6729942. DOI: 10.1523/JNEUROSCI.3213-04.2004. View

19.

Hamdan F, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S . Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation. N Engl J Med. 2009; 360(6):599-605. PMC: 2925262. DOI: 10.1056/NEJMoa0805392. View

20.

Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham D . SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. Neuron. 2004; 43(4):563-74. DOI: 10.1016/j.neuron.2004.08.003. View