Cav3.1 T‐Type Calcium Channel Acts as a Gateway for GABAergic Excitation in the Medial Prefrontal Cortex That Leads to Chronic Psychological Stress Responses in Mice

Aim The molecular mechanisms of chronic stress‐induced psychiatric disorders, including depression, remain unknown. The current study aimed to assess the role of Cav3.1 T‐type calcium channels as a gateway for the chronic stress‐induced activation of parvalbumin (PV)‐positive gamma‐aminobutyric acidergic (GABAergic) neurons in the medial prefrontal cortex (mPFC) of mice. Methods The function of the Cav3.1 T‐type calcium channel in the mouse mPFC following chronic stress was investigated using behavioral tests, electrophysiological analyses, transcriptome analyses, and optogenetic approaches. Results Cav3.1‐knockout (Cav3.1−/−) mice were resistant to chronic stress‐induced depressive‐like behaviors induced by repeated forced‐swimming test or tail‐suspension test. Immunohistochemical analysis revealed that Cav3.1 was predominantly localized in PV‐positive GABAergic neurons in the mPFC. Based on transcriptomic and electrophysiological analyses, the excitatory–inhibitory (E–I) balance was disrupted by the chronic stress‐induced activation of PV‐positive GABAergic neurons in the mPFC of wild‐type (WT) mice, but not in that of Cav3.1−/− mice. Optogenetic control of PV‐positive GABAergic neurons in the mPFC revealed that they played a pivotal role in depressive‐like behaviors. The administration of TTA‐A2, a selective T‐type calcium channel antagonist, reduced chronic stress‐induced depressive‐like behaviors. Conclusion The Cav3.1 T‐type calcium channel acts as a gateway for the activation of GABAergic neurons in the mPFC of mice, thereby eliciting chronic psychobiological stress responses.