Autism and Schizophrenia-Associated CYFIP1 Regulates the Balance of Synaptic Excitation and Inhibition

Summary

Altered excitatory/inhibitory (E/I) balance is implicated in neuropsychiatric and neurodevelopmental disorders, but the underlying genetic etiology remains poorly understood. Copy number variations in CYFIP1 are associated with autism, schizophrenia, and intellectual disability, but its role in regulating synaptic inhibition or E/I balance remains unclear. We show that CYFIP1, and the paralog CYFIP2, are enriched at inhibitory postsynaptic sites. While CYFIP1 or CYFIP2 upregulation increases excitatory synapse number and the frequency of miniature excitatory postsynaptic currents (mEPSCs), it has the opposite effect at inhibitory synapses, decreasing their size and the amplitude of miniature inhibitory postsynaptic currents (mIPSCs). Contrary to CYFIP1 upregulation, its loss in vivo, upon conditional knockout in neocortical principal cells, increases expression of postsynaptic GABA _A receptor β2/3-subunits and neuroligin 3, enhancing synaptic inhibition. Thus, CYFIP1 dosage can bi-directionally impact inhibitory synaptic structure and function, potentially leading to altered E/I balance and circuit dysfunction in CYFIP1-associated neurological disorders.

Graphical Abstract

Highlights

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  CYFIP1 and CYFIP2 are enriched at inhibitory synapses.

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  CYFIP1 upregulation differentially disrupts inhibitory and excitatory synapses.

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  Conditional loss of CYFIP1 alters neuroligin 3 and GABA _AR β-subunits expression.

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  Loss of CYFIP1 increases inhibitory synaptic clusters and hence mIPSC amplitude.

Abstract

Copy number variations (CNVs) in CYFIP1 are associated with neuropsychiatric disorders. Davenport et al. uncover an essential role for CYFIP1 in regulating synaptic inhibition and in maintaining the excitatory/inhibitory balance. By altering CYFIP1 gene dosage, to model CNV, they reveal important bi-directional effects on inhibitory transmission in hippocampal neurons.