Mouse models of

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• SYNGAP1 mutations are a leading genetic cause of neurodevelopmental disorders (NDD), specifically SYNGAP1-related intellectual disability (SRID).
• SRID is characterized by cognitive impairment, social deficits, seizures, and sleep disturbances.
• Previous studies in rodents highlighted Syngap1's role in synaptic plasticity and function, but in vivo models for specific human mutations were lacking.

Approach:

• Utilized CRISPR-cas9 to generate two knock-in mouse models for distinct SRID-causal SYNGAP1 variants.
• One model features a frameshift mutation (SYNGAP1; L813RfsX22), and the other an intronic mutation creating a cryptic splice acceptor site (SYNGAP1; c.3583-9G>A).
• Assessed Syngap1 mRNA and protein levels, synaptic plasticity, and behavioral phenotypes.

Key Points:

• Both mouse models exhibited reduced Syngap1 mRNA (30-50%) and approximately 50% reduction in Syngap1 protein.
• Deficits in synaptic plasticity and key SRID behavioral phenotypes, including hyperactivity and impaired working memory, were observed.
• RNA-seq confirmed cryptic splice site activity and revealed transcriptional changes consistent with Syngap1+/- mice.

Conclusions:

• These findings suggest that a 50% reduction in SYNGAP1 protein is critical for SRID pathogenesis.
• The generated SRID mouse models serve as a valuable resource for studying the disorder.
• These models establish a framework for developing targeted therapeutic strategies for SRID.