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.