SynGAP isoforms differentially regulate synaptic plasticity and dendritic development.

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

doi:10.7554/elife.56273

Abstract

SynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: α1, α2, β, and γ. 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-α1, which undergoes liquid-liquid phase separation with PSD-95, is highly enriched in synapses and is required for LTP. In contrast, SynGAP-β, which does not bind PSD-95 PDZ domains, is less synaptically targeted and promotes dendritic arborization. A mutation in SynGAP-α1 that disrupts phase separation and synaptic targeting abolishes its ability to regulate plasticity and instead causes it to drive dendritic development like SynGAP-β. 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.

Highlights

SynGAP is a GTPase-activating protein (GAP) that is highly enriched in dendritic spines of excitatory neurons (Chen et al, 1998; Kim et al, 1998)
We previously demonstrated that SynGAP-a1 undergoes rapid NMDAR- and CaMKII-dependent dispersion from the synapse, and this dispersion is required for synaptic AMPAR insertion and spine enlargement that occur during long-term potentiation (LTP) (Araki et al, 2015)
We find SynGAP-a1 to be uniquely critical for LTP expression

Summary

Introduction

SynGAP is a GTPase-activating protein (GAP) that is highly enriched in dendritic spines of excitatory neurons (Chen et al, 1998; Kim et al, 1998). We report that SynGAP-a1 constitutes only 25–35% of total SynGAP protein in the brain, underscoring the importance of characterizing how the C-terminal SynGAP splice variants contribute to neuronal and synaptic development that are associated with the pathogenesis of SYNGAP1 haploinsufficiency. We identify isoform-specific differences in biochemical interactions between SynGAP and PSD-95, and show how these differences are related to the functional mode of each isoform, regulating either synaptic plasticity or dendritic structure. These results suggest that individual SynGAP isoforms mediate distinct, specialized regulation of neuronal and synaptic development and will inform potential therapeutic strategies for treating SYNGAP1-related disorders

Results

E Mouse Brain Region

SynGAPβ 2 0

Discussion

Materials and methods

Funding Funder National Institutes of Health