Syngap isoforms differentially regulate synaptic plasticity and dendritic development

Yoichi Araki, Ingie Hong, Timothy R. Gamache, Shaowen Ju, Leonardo Collado-Torres, Joo Heon Shin, Richard L. Huganir

Research output: Contribution to journalArticlepeer-review

Abstract

SynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: a1, a2, b, and g. Although studies have implicated SYNGAP1 in several cognitive disorders, it is not clear which SynGAP isoforms contribute to disease. Here, we demonstrate that SynGAP isoforms exhibit unique spatiotemporal expression patterns and play distinct roles in neuronal and synaptic development in mouse neurons. SynGAP-a1, which undergoes liquid-liquid phase separation with PSD-95, is highly enriched in synapses and is required for LTP. In contrast, SynGAP-b, which does not bind PSD-95 PDZ domains, is less synaptically targeted and promotes dendritic arborization. A mutation in SynGAP-a1 that disrupts phase separation and synaptic targeting abolishes its ability to regulate plasticity and instead causes it to drive dendritic development like SynGAP-b. These results demonstrate that distinct intrinsic biochemical properties of SynGAP isoforms determine their function, and individual isoforms may differentially contribute to the pathogenesis of SYNGAP1-related cognitive disorders.

Original languageEnglish (US)
Article numbere56273
Pages (from-to)1-28
Number of pages28
JournaleLife
Volume9
DOIs
StatePublished - Jun 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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