Endogenous Syngap1 alpha splice forms promote cognitive function and seizure protection.

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Loss-of-function variants in the *SYNGAP1* gene are linked to developmental encephalopathy, characterized by cognitive impairment, autistic features, and epilepsy.
• SynGAP proteins are encoded by *SYNGAP1* and exist in distinct functional isoforms due to alternative splicing, which imparts varied cellular functions.
• The in vivo roles of these different *SYNGAP1* splice sequences in regulating neuronal function and behavior remain largely unexplored.

Purpose of the Study:

• To investigate the in vivo function of *SYNGAP1* splice variants, specifically the α1 and α2 C-terminal motifs, in regulating neuronal function and behavior.
• To determine the impact of altered expression and function of SynGAP isoforms on cognitive abilities and seizure susceptibility.

Main Methods:

• Utilized mouse models with altered expression of SynGAP-α1/2 C-terminal splice variants.
• Generated mice with α1-specific mutations to disrupt SynGAP cellular functions without altering overall protein expression.
• Assessed phenotypes including survival, learning, seizure latency, and synapse plasticity.

Main Results:

• Reduced expression of SynGAP-α1/2 variants in mice led to severe phenotypes, including decreased survival, impaired learning, and reduced seizure latency.
• Upregulation of α1/2 expression in mice improved learning and increased seizure latency.
• α1-specific mutations impaired learning, promoted seizures, and disrupted synapse plasticity, despite normal protein expression levels.

Conclusions:

• Endogenous SynGAP isoforms containing α1/2 spliced sequences are essential for promoting cognitive function and providing seizure protection.
• The regulation of SynGAP-α expression or function represents a potential therapeutic strategy for improving cognitive deficits and mitigating seizures in related disorders.