Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection
- The Scripps Research Institute, United States
- University of California, Irvine, United States
- University of Southern California, United States
- Institut d'Investigació Biomèdica Sant Pau, Spain
- Johns Hopkins School of Medicine, United States
Abstract
Loss-of-function variants in SYNGAP1 cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. SYNGAP1 splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs. However, it remains unknown how these different splice sequences function in vivo to regulate neuronal function and behavior. Reduced expression of SynGAP-a1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of a1/2 expression improved learning and increased seizure latency. Mice expressing a1-specific mutations, which disrupted SynGAP cellular functions without altering protein expression, promoted seizure, disrupted synapse plasticity, and impaired learning. These findings demonstrate that endogenous SynGAP isoforms with a1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-a expression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for western blots and mass spec experiments.
Article and author information
Author details
Funding
National Institute of Mental Health (MH096847 ; MH108408)
- Gavin Rumbaugh
Autism Speaks (#10646)
- Murat Kilinc
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#15-037 and #15-038) of Scripps Florida.
Copyright
© 2022, Kilinc et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection
eLife 11:e75707.
https://doi.org/10.7554/eLife.75707
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