Genetic variants of the cytoplasmic FMR1‐interacting protein 2 (CYFIP2 ) encoding an actin‐regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2 ‐associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2 +/− ) mice to understand their neurobehavioral phenotypes and underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2 +/− mice and specified a neuronal function mediating its efficacy.
We performed behavioral analyses on Cyfip2 +/− mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses on Cyfip2 +/− prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with viral injections.
Adult Cyfip2 +/− mice exhibited lithium‐responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2 +/− PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2 +/− mice showed increased seizure susceptibility and auditory steady‐state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2 +/− L5 neurons. RNA‐sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2 +/− PFC. Viral‐mediated CYFIP2 reduction in the PFC was sufficient to induce L5 hyperexcitability and lithium‐responsive abnormal behavior.
These results suggest that L5‐specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and lithium‐mediated amelioration of neurobehavioral phenotypes in adult Cyfip2 +/− mice, which can be implicated in CYFIP2 ‐associated brain disorders.