Journal Article

Adolescent sleep defects and dopaminergic hyperactivity in mice with a schizophrenia-linked Shank3 mutation

de Lecea, Luis, González, Oscar C, Bian, Wen-Jie

2023

Overview

Abstract Shank3 is a shared risk gene for autism spectrum disorders and schizophrenia. Sleep defects have been characterized for autism models with Shank3 mutations; however, evidence has been lacking for the potential sleep defects caused by Shank3 mutation associated with schizophrenia and how early in development these defects may occur. Here we characterized the sleep architecture of adolescent mice carrying a schizophrenia-linked, R1117X mutation in Shank3. We further employed GRABDA dopamine sensor and fiber photometry to record dopamine release in the nucleus accumbens during sleep/wake states. Our results show that homozygous mutant R1117X mice have significantly reduced sleep in the dark phase during adolescence, altered electroencephalogram power, especially during the rapid-eye-movement sleep, and dopamine hyperactivity during sleep but not during wakefulness. Further analyses suggest that these adolescent defects in sleep architecture and dopaminergic neuromodulation tightly correlate with the social novelty preference later in adulthood and predict adult social performance during same-sex social interactions. Our results provide novel insights into the sleep phenotypes in mouse models of schizophrenia and the potential use of developmental sleep as a predictive metric for adult social symptoms. Together with recent studies in other Shank3 models, our work underscores the idea that Shank3-involved circuit disruptions may be one of the shared pathologies in certain types of schizophrenia and autism. Future research is needed to establish the causal relationship among adolescent sleep defects, dopaminergic dysregulation, and adult behavioral changes in Shank3 mutation animals and other models. Graphical abstract Graphical Abstract

• Publisher: Oxford University Press
• Subject: Adolescence / Analysis / Animal behavior / Animals / Autism / Autism Spectrum Disorder - genetics / Child psychopathology / Dopamine / Genetic aspects / Hyperactivity / Insomnia and Psychiatric Disorders / Mice / Microfilament Proteins - genetics / Mutation / Mutation - genetics / Nerve Tissue Proteins - genetics / REM sleep / Schizophrenia / Schizophrenia - complications / Schizophrenia - genetics / Sleep / Sleep deprivation / Social aspects