Cognitive decline and synaptopathy in X-linked moesin knock-out mice

Abstract

Abstract Moesin-like gene 1 antisense was increased in the postmortem cortex of patients with autism spectrum disorders. Overexpression of moesin-like gene 1 antisense induces downregulation of moesin expression in cortical neurons, resulting in decreased neurite numbers and length. However, moesin knockout (KO) mice have not been reported about behavioral abnormalities or delayed brain development, indicating autism spectrum disorders. Here, we generated moesin KO mice by using the CRISPR/CAS9 system and observed their behaviors. Moesin KO mice exhibited abnormal developmental behaviors at 7 days, cognitive decline in the passive avoidance and Y maze tests, and anxiety symptoms in the open field test compared to wild-type mice at 3 months. Moreover, the primary cortical neurons of moesin KO mice showed a low cell survival rate and low expression of proteins involved in neuronal development and growth, such as MAP2, DCX, SOX2, SNAP25, and PSD95. Western blot analysis also revealed the downregulation of various synaptic proteins, such as syntaxin 1A and CDK5, in the brain of moesin KO adult mice. Moreover, the phosphorylation levels of synapsin I, MUNC18, ERK, and CREB were downregulated in the brains of moesin-KO mice. Furthermore, risperidone reversed the impaired memory function and synapsin I and ERK phosphorylation in the cortical tissue of moesin-KO mice. Thus, these results suggest that moesin affects neurodevelopmental and cognitive processes, plays an important role in the synaptic plasticity showing normal synapse structure and function, and that risperidone can reverse these synaptopathy and neurodevelopmental disorders.