Cyfip1 Regulates SynGAP1 at Hippocampal Synapses
Abhishek Sahasrabudhe1, Fatema Begum1, Christopher A Guevara1,2
1Icahn School of Medicine at Mount Sinai, Nash Family Department of Neuroscience, Friedman Brain Institute, New York, NY, United States.
Frontiers in Synaptic Neuroscience
|February 22, 2021
Summary
Cyfip1 deficiency lowers synaptic SynGAP1 levels in mice, impacting synapse maturation and actin dynamics. This interaction may explain shared roles in neurodevelopmental disorders like intellectual disability and autism.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Copy number variations in CYFIP1 and haploinsufficiency of SYN বাহGAP1 are linked to intellectual disability, autism, and schizophrenia.
- Both Cyfip1 and SynGAP1 regulate synapse maturation in the hippocampus and influence mGluR-dependent long-term depression.
- Cyfip1 inhibits protein translation and promotes actin polymerization; SynGAP1 is a synaptically localized Ras/Rap GTPase-activating protein (GAP).
Purpose of the Study:
- To investigate how Cyfip1 haploinsufficiency affects SynGAP1 levels and localization in the mouse hippocampus.
- To identify potential molecular mechanisms underlying the interaction between Cyfip1 and SynGAP1.
Main Methods:
- Analysis of synaptic and total SynGAP1 levels in Cyfip1+/- mice during postnatal development and adulthood.
- Assessment of kinase activity (Cdk5, CaMKII) and GTPase activity (Rac1) in hippocampal tissue.
- Evaluation of actin dynamics, including F-actin levels and WAVE regulatory complex activity.
- Measurement of synaptic protein levels (GluA2, mGluR1/5) and AMPA receptor-mediated responses.
Main Results:
- Synaptic SynGAP1 levels were significantly reduced in Cyfip1+/- mice compared to wild-type controls.
- Reduced Cdk5 levels and maintained CaMKII activity were observed in Cyfip1+/- mice.
- Increased Rac1 activity and enhanced synaptic F-actin levels were detected, partly due to increased WAVE regulatory complex activity.
- Elevated synaptic GluA2 and mGluR1/5 levels, along with increased AMPA receptor-mediated responses, were found in Cyfip1+/- mice.
Conclusions:
- Cyfip1 haploinsufficiency leads to decreased synaptic levels of SynGAP1 in the mouse hippocampus.
- The interaction involves altered kinase activity and actin dynamics, suggesting Cyfip1 regulates SynGAP1.
- These findings highlight a coordinated function of Cyfip1 and SynGAP1 at synapses, influencing actin polymerization and GAP activity, potentially relevant to neurodevelopmental disorders.
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