TY - JOUR
T1 - Syngap isoforms differentially regulate synaptic plasticity and dendritic development
AU - Araki, Yoichi
AU - Hong, Ingie
AU - Gamache, Timothy R.
AU - Ju, Shaowen
AU - Collado-Torres, Leonardo
AU - Shin, Joo Heon
AU - Huganir, Richard L.
N1 - Funding Information:
We thank all members of the Huganir lab for discussion and support throughout this work especially Drs. Kacey Rajkovich, Elizabeth Gerber, Megnan Tian, Bian Liu, and Rich Johnson for critical experimental help and preparation of the manuscript. We also thank Andrew E Jaffe, and Daniel R Wein-berger for help with acquiring and analyzing of RNAseq data. This work was supported by grants from National Institute of Health (MH112151, NS036715) and the SynGAP Research Fund. We want to thank the Bridge The Gap SYNGAP Education and Research Foundation, the SynGAP Research Fund, and all of the SynGAP patient families for their outreach and advocacy.
Publisher Copyright:
© Araki et al.
PY - 2020/6
Y1 - 2020/6
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.56273
DO - 10.7554/eLife.56273
M3 - Article
C2 - 32579114
AN - SCOPUS:85087032694
SN - 2050-084X
VL - 9
SP - 1
EP - 28
JO - eLife
JF - eLife
M1 - e56273
ER -