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<p>The cross-disorder risk gene <i>CACNA1C</i> encoding the α1 subunit of the L-type calcium channel Ca<sub>v</sub>1.2 has repeatedly been associated with various psychiatric disorders. <i>Cacna1c</i> is expressed in parvalbumin positive (PV<sup>+</sup>) 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<sub>v</sub>1.2 to endophenotypes related to psychiatric disorders, we generated mice with a conditional <i>Cacna1c</i> deletion in PV<sup>+</sup> neurons (Ca<sub>v</sub>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<sub>v</sub>1.2 in forebrain glutamatergic neurons (Ca<sub>v</sub>1.2-Nex) displayed enhanced active stress-coping, revealing a bidirectional, cell type-specific role of Ca<sub>v</sub>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<sub>v</sub>1.2 in PV<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月20日

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  • Srivaishnavi Loganathan,
  • Chen Zhao,
  • Jan M. Deussing

摘要

The cross-disorder risk gene CACNA1C encoding the α1 subunit of the L-type calcium channel Cav1.2 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 Cav1.2 to endophenotypes related to psychiatric disorders, we generated mice with a conditional Cacna1c deletion in PV+ neurons (Cav1.2-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 Cav1.2 in forebrain glutamatergic neurons (Cav1.2-Nex) displayed enhanced active stress-coping, revealing a bidirectional, cell type-specific role of Cav1.2 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 Cav1.2 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.