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Cacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1.

TitleCacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1.
Publication TypeJournal Article
Year of Publication2017
AuthorsKabir ZD, Lee AS, Burgdorf CE, Fischer DK, Rajadhyaksha AM, Mok E, Rizzo B, Rice RC, Singh K, Ota KT, Gerhard DM, Schierberl KC, Glass MJ, Duman RS, Rajadhyaksha AM
JournalNeuropsychopharmacology
Volume42
Issue10
Pagination2032-2042
Date Published2017 Sep
ISSN1740-634X
Abstract

The CACNA1C gene that encodes the L-type Ca2+ channel (LTCC) Cav1.2 subunit has emerged as a candidate risk gene for multiple neuropsychiatric disorders including bipolar disorder, major depressive disorder, and schizophrenia, all marked with depression-related symptoms. Although cacna1c heterozygous (HET) mice have been previously reported to exhibit an antidepressant-like phenotype, the molecular and circuit-level dysfunction remains unknown. Here we report that viral vector-mediated deletion of cacna1c in the adult prefrontal cortex (PFC) of mice recapitulates the antidepressant-like effect observed in cacna1c HET mice using the sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST). Molecular studies identified lower levels of REDD1, a protein previously linked to depression, in the PFC of HET mice, and viral-mediated REDD1 overexpression in the PFC of these HET mice reversed the antidepressant-like effect in SPT and TST. Examination of downstream REDD1 targets found lower levels of active/phosphorylated Akt (S473) with no change in mTORC1 phosphorylation. Examination of the transcription factor FoxO3a, previously linked to depression-related behavior and shown to be regulated in other systems by Akt, revealed higher nuclear levels in the PFC of cacna1c HET mice that was further increased following REDD1-mediated reversal of the antidepressant-like phenotype. Collectively, these findings suggest that REDD1 in cacna1c HET mice may influence depression-related behavior via regulation of the FoxO3a pathway. Cacna1c HET mice thus serve as a useful mouse model to further study cacna1c-associated molecular signaling and depression-related behaviors relevant to human CACNA1C genetic variants.

DOI10.1038/npp.2016.271
Alternate JournalNeuropsychopharmacology
PubMed ID27922594
PubMed Central IDPMC5561335