Gene-environment interactions mediate stress susceptibility and resilience through the CaMKIIβ/TARPγ-8/AMPAR pathway

Although stressful events predispose individuals to psychiatric disorders, such as depression, not all people who undergo a stressful life experience become depressed, suggesting that gene-environment interactions (GxE) determine depression risk. The ventral hippocampus (vHPC) plays key roles in motivation, sociability, anhedonia, despair-like behaviors, anxiety, sleep, and feeding, pointing to the involvement of this brain region in depression. However, the molecular mechanisms underlying the cross talk between the vHPC and GxE in shaping behavioral susceptibility and resilience to chronic stress remain elusive. Here, we show that Ca2+/calmodulin-dependent protein kinase II beta (CaMKII beta) activity in the vHPC is differentially modulated in GxE mouse models of depression susceptibility and resilience, and that CaMKII beta-mediated TARP gamma-8 phosphorylation enhances the expression of AMPA receptor subunit GluA1 in the postsynaptic sites to enable stress resilience. We present previously missing molecular mechanisms underlying chronic stress-elicited behavioral changes, providing strategies for preventing and treating stress-related psychiatric disorders.

Automated summary

The study explores the role of CaMKII beta in the ventral hippocampus in depression susceptibility and resilience, revealing that its modulation of TARP gamma-8 phosphorylation enhances stress resilience by increasing the expression of AMPA receptor subunit GluA1. These findings provide new insights into the molecular mechanisms underlying chronic stress-induced behavioral changes and offer strategies for preventing and treating stress-related psychiatric disorders.