Protocadherin 10, a member of cadherin superfamily, increases stress-susceptibility in chronic unpredictable stress-treated rats.

Depression is a debilitating disorder influenced by individual variation in stress susceptibility. The identification of stress-sensitive and stress-resistant phenotypes is critical for understanding its pathogenesis. We previously identified several proteins associated with these phenotypes, yet their functional roles remain unclear. Here, we investigated whether protocadherin 10 (PCDH10), a brain-enriched non-clustered protocadherin, underlies individual differences in stress susceptibility. Rats were subjected to chronic unpredictable stress and classified as stress-sensitive or stress-resistant individuals based on sucrose preference. We found that PCDH10 mRNA and protein levels were significantly downregulated in the medial prefrontal cortex of stress-sensitive rats but upregulated in stress-resistant rats compared to controls. Conversely, opposing expression patterns were observed in the hippocampus. Functional studies demonstrated that PCDH10 overexpression in the hippocampus promoted depression-like behaviors, whereas its knockdown exerted a protective, antidepressant-like effect. Our findings reveal PCDH10 as a key region-specific regulator of stress susceptibility. Targeted inhibition of PCDH10 in the hippocampus represents a promising new therapeutic strategy for depression.