Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection
Murat Kilinc, Vineet Arora, Thomas K Creson, Camilo Rojas, Aliza A Le, Julie Lauterborn, Brent Wilkinson, Nicolas Hartel, Nicholas Graham, Adrian Reich, Gemma Gou, Yoichi Araki, Àlex Bayés, Marcelo Coba, Gary Lynch, Courtney A Miller, Gavin Rumbaugh
Abstract
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-α1/2 C-terminal splice variants in mice caused severe phenotypes, including reduced survival, impaired learning, and reduced seizure latency. In contrast, upregulation of α1/2 expression improved learning and increased seizure latency. Mice expressing α1-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 α1/2 spliced sequences promote cognitive function and impart seizure protection. Regulation of SynGAP-αexpression or function may be a viable therapeutic strategy to broadly improve cognitive function and mitigate seizure.