Astrocyte Ezrin defines resilience to stress-induced depressive behaviours in mice

Astrocyte atrophy is the main histopathological hallmark of major depressive disorder (MDD) in humans and in animal models of depression. Here we demonstrated that manipulating Ezrin expression specifically in astrocytes significantly increases the resilience of mice to chronic unpredictable mild stress (CUMS). Overexpression of Ezrin in astrocytes from the medial prefrontal cortex (mPFC) rescued depressive-like behaviours induced by CUMS, whereas down-regulation of Ezrin in astrocytes from the mPFC increased mouse susceptibility to CUMS and promoted depressive-like behaviours. These behavioural changes correlated with astrocytic morphology. Astrocytes from the mPFC of mice sensitive to CUMS demonstrated significant atrophy; similar atrophy was found in astrocytes from animals with down-regulated Ezrin expression. On the contrary, morphology of astrocytes remained unchanged in animals resistant to CUMS and in animals with astrocytic overexpression of Ezrin. Morphological changes also correlated with Ezrin immunoreactivity, which was low in mice with depressive-like behaviours and high in mice resistant to stress. We conclude that Ezrin-dependent morphological remodelling of astrocytes defines the sensitivity of mice to stress; high Ezrin expression renders them stress resilient, whereas low Ezrin expression promotes depressive-like behaviour in response to chronic stress.