Authors
Walsh, J. D., Scala Chavez, D., Lee, A. S., Martinez-Rivera, A., Rajadhyaksha, A. M.
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-specific behavioral consequences of Cacna1c loss in D1 cells. We find that D1-Cacna1c deletion produces a sex- and gene dosage-dependent effect on fear memory. In males, homozygous loss of D1-Cacna1c heightens remote contextual fear at 30-days post-training, replicating prior findings, whereas partial loss had no effect. Cue-associated fear memory remained unaffected across genotypes. In contrast, females exhibited heightened contextual fear with both heterozygous and homozygous D1-Cacna1c loss at 24-hrs, 7-days, and 30-days post-training, indicating increased sensitivity to contextual aversive learning. Cue-associated fear memory was higher at 24-hrs but normalized at later time points in females. In the Water Y-maze, males with heterozygous or homozygous D1-Cacna1c loss showed impaired spatial memory at 7-days post-training, whereas females were unaffected. D1-Cacna1c deletion reduced locomotor activity selectively in females during the initial 5-mins of a 60-min session, with no genotype effects in males. Social interaction and anxiety-like behavior were unchanged across groups. Together, these findings highlight the interplay between dopamine receptor signaling and calcium channel function in shaping sex-dependent aspects of memory.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 03 Nov 2025.
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