Cacna1c deficiency in parvalbumin-expressing neurons promotes anxiety and passive stress-coping behavior

Abstract

Abstract The cross-disorder risk gene CACNA1C encoding the α1 subunit of the L-type calcium channel Ca v 1.2 has repeatedly been associated with various psychiatric disorders. Cacna1c is expressed in parvalbumin positive (PV + ) neurons which play an important role in regulating excitation-inhibition (E/I) balance and their dysregulation has been implicated in different psychiatric conditions. To address the cell type-specific contribution of Ca v 1.2 to endophenotypes related to psychiatric disorders, we generated mice with a conditional Cacna1c deletion in PV + neurons (Ca v 1.2-PV). Male knockout mice exhibited increased anxiety-like behavior, and a more passive stress-coping strategy in the forced swim test, while locomotion, social behavior, and cognitive performance were unaffected. In contrast, mice lacking Ca v 1.2 in forebrain glutamatergic neurons (Ca v 1.2-Nex) displayed enhanced active stress-coping, revealing a bidirectional, cell type-specific role of Ca v 1.2 in stress-induced behaviors. cFos mapping following stress exposure identified distinct activation patterns in stress-responsive brain regions, suggesting distinct circuit mechanisms underlying these opposing behavioral phenotypes. Together, these findings identify Ca v 1.2 in PV + neurons as a critical regulator of anxiety and stress-coping behavior and highlight complementary contributions of inhibitory and excitatory circuits to stress adaptation, with implications for targeted therapeutic strategies in psychiatric disorders.