Cacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1.
Neuropsychopharmacology
; 42(10): 2032-2042, 2017 Sep.
Article
en En
| MEDLINE
| ID: mdl-27922594
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
/
Corteza Prefrontal
/
Canales de Calcio Tipo L
/
Trastorno Depresivo
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Neuropsychopharmacology
Asunto de la revista:
NEUROLOGIA
/
PSICOFARMACOLOGIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos