Deletion of Cacna1c (Ca V 1.2) in D1-expressing cells elicits divergent sex-specific effects on aversive and spatial memories.

Overview

abstract

Dopamine signaling is critical for cognitive and emotional regulation and is implicated in multiple neuropsychiatric disorders. One downstream effector of dopamine is the L-type calcium channel CaV1.2, encoded by the risk gene CACNA1C. Genome-wide association studies have consistently linked CACNA1C single nucleotide polymorphisms to schizophrenia, bipolar disorder, and related conditions. We previously showed that homozygous deletion of Cacna1c in dopamine receptor 1 (D1)-expressing cells enhances remote (30 days post-training) contextual fear memory in male mice. Here, we extend these findings by examining sex- and gene dosage-dependent behavioral consequences of Cacna1c loss in D1 cells. We find a sex-dependent dissociation, where females show enhanced aversive memory up to 30 days post-training even with partial Cacna1c loss, whereas males require complete loss to show enhanced fear. In contrast, males show impaired spatial memory in the Water Y-maze following heterozygous or homozygous deletion, an effect not observed in females. Cue-associated fear memory was transiently elevated in females but unaffected in males. Locomotor activity was reduced in females during the initial minutes of testing, with no effects in males, while social interaction and anxiety-like behaviors were unchanged across groups. These findings indicate that Ca _v 1.2 signaling in D1-expressing cells differentially regulates aversive versus spatial memory in a sex-dependent manner, providing insight into how CACNA1C risk variants may contribute to sex-specific cognitive phenotype.