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Mouse models of SYNGAP1-related intellectual disability
Yoichi Araki1, Elizabeth E Gerber1, Kacey E Rajkovich1
1Department of Neuroscience, Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Summary
Mutations in SYNGAP1 cause SYNGAP1-related intellectual disability (SRID). New mouse models show that reducing SynGAP1 protein by half leads to synaptic deficits and SRID symptoms, offering insights for therapeutic strategies.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- De novo loss-of-function mutations in SYNGAP1 are a primary genetic cause of neurodevelopmental disorders (NDDs).
- SYNGAP1-related intellectual disability (SRID) presents with cognitive impairment, social deficits, seizures, and sleep disturbances.
- Previous studies in rodents indicated Syngap1's role in synaptic plasticity, learning, and memory.
Purpose of the Study:
- To investigate the in vivo effects of specific human SYNGAP1 mutations linked to SRID.
- To create and characterize novel mouse models for studying SRID pathogenesis.
- To determine the impact of reduced SYNGAP1 protein levels on synaptic function and behavior.
Main Methods:
- Utilized CRISPR-Cas9 gene editing to generate knock-in mouse models for two distinct SRID-causative SYNGAP1 variants.
- Quantified SYNGAP1 mRNA and protein levels in the generated models.
- Assessed synaptic plasticity, working memory, and hyperactivity in the mutant mice.
Main Results:
- Both mouse models exhibited approximately 50% reduction in Syngap1 protein levels.
- Deficits in synaptic plasticity, impaired working memory, and hyperactivity were observed in the mutant mice.
- These findings suggest that a 50% reduction in SYNGAP1 protein is critical for SRID pathogenesis.
Conclusions:
- The generated SYNGAP1 knock-in mouse models accurately recapitulate key features of SRID.
- These models serve as a valuable resource for understanding SRID and developing therapeutic interventions.
- Reducing SYNGAP1 protein by approximately 50% is identified as a key factor in the disease mechanism.
