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SynGAP splice isoforms differentially regulate synaptic plasticity and dendritic development

View ORCID ProfileYoichi Araki, View ORCID ProfileIngie Hong, Timothy R. Gamache, Shaowen Ju, Leonardo Collado-Torres, Joo Heon Shin, View ORCID ProfileRichard L. Huganir
doi: https://doi.org/10.1101/2020.01.28.922013
Yoichi Araki
Johns Hopkins University School of Medicine, Department of Neuroscience, Kavli Neuroscience Discovery Institute
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Ingie Hong
Johns Hopkins University School of Medicine, Department of Neuroscience, Kavli Neuroscience Discovery Institute
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Timothy R. Gamache
Johns Hopkins University School of Medicine, Department of Neuroscience, Kavli Neuroscience Discovery Institute
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Shaowen Ju
Johns Hopkins University School of Medicine, Department of Neuroscience, Kavli Neuroscience Discovery Institute
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Leonardo Collado-Torres
Johns Hopkins University School of Medicine, Department of Neuroscience, Kavli Neuroscience Discovery Institute
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Joo Heon Shin
Johns Hopkins University School of Medicine, Department of Neuroscience, Kavli Neuroscience Discovery Institute
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Richard L. Huganir
Johns Hopkins University School of Medicine, Department of Neuroscience, Kavli Neuroscience Discovery Institute
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  • ORCID record for Richard L. Huganir
  • For correspondence: rhuganir@jhmi.edu
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Summary

SynGAP is a synaptic Ras GTPase-activating protein (GAP) with four C-terminal splice variants: α1, α2, β, and γ. Although recent studies have implicated SYNGAP1 haploinsufficiency in ID/ASD pathogenesis, the degree to which each SynGAP isoform contributes to disease pathogenesis remains elusive. Here we demonstrate that individual SynGAP isoforms exhibit unique spatiotemporal expression and have distinct roles in neuronal and synaptic development. The SynGAP-α1 isoform, which undergoes robust liquid-liquid phase-separation with PSD-95 and is highly-enriched in synapses, is expressed late in development and disperses from synaptic spines in response to LTP-inducing synaptic activity to allow for AMPA receptor insertion and spine enlargement. In contrast, the SynGAP-β isoform, which undergoes less liquid-liquid phase-separation with PSD95 and is less synaptically targeted, is expressed early in development and promotes dendritic arborization. Interestingly, a SynGAP-α1 mutation that disrupts phase separation and synaptic targeting abolishes its function in plasticity and instead drives dendritic arbor development like the β isoform. These results demonstrate that distinct phase separation and synaptic targeting properties of SynGAP isoforms determine their function.

Highlights

  1. SynGAP-α1, α2, β, γ isoforms have distinct spatiotemporal expression and function in the brain.

  2. SynGAP-α1 is required for plasticity, while β is required for dendritic development.

  3. Liquid-liquid phase separation of SynGAP-α1 is required for its role in plasticity.

  4. SynGAP isoforms may differentially contribute to SYNGAP1 related human NDDs.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 30, 2020.
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SynGAP splice 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
bioRxiv 2020.01.28.922013; doi: https://doi.org/10.1101/2020.01.28.922013
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SynGAP splice 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
bioRxiv 2020.01.28.922013; doi: https://doi.org/10.1101/2020.01.28.922013

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