{"doi":"10.1101/2025.10.31.684545","title":"Deletion of <i>Cacna1c</i> (Ca <sub>V</sub> 1.2) in D1-expressing cells elicits divergent sex-specific effects on aversive and spatial memories","abstract":"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 Ca V 1.2, 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":579748,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9542,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":527661,"name":"D. Chavez","orcid":null,"position":1,"is_corresponding":false},{"id":1490268,"name":"A S Lee","orcid":"0000-0003-4874-1767","position":2,"is_corresponding":false},{"id":440210,"name":"Arlene Martínez-Rivera","orcid":"0000-0002-4180-1635","position":3,"is_corresponding":false},{"id":344892,"name":"Anjali M. Rajadhyaksha","orcid":"0000-0002-8399-5466","position":4,"is_corresponding":false},{"id":1490267,"name":"Julia M. Walsh","orcid":"0009-0000-7790-6116","position":0,"is_corresponding":true}],"reference_count":68,"raw_metadata":null,"created_at":"2026-07-19T02:58:34.718602Z","pmid":"41279574","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}