Title | Cacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Kabir 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 |
Journal | Neuropsychopharmacology |
Date Published | 2017 Jan 04 |
ISSN | 1740-634X |
Abstract | The CACNA1C gene that encodes the L-type Ca(2+) 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.Neuropsychopharmacology advance online publication, 4 January 2017; doi:10.1038/npp.2016.271. |
DOI | 10.1038/npp.2016.271 |
Alternate Journal | Neuropsychopharmacology |
PubMed ID | 27922594 |