title: Cacna1c in the Prefrontal Cortex Regulates Depression-Related Behaviors via REDD1.
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.
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Zeeba D
authors.initials: ZD
authors.lastname: Kabir
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.|Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Anni S
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.|Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Burgdorf
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Delaney K
authors.initials: DK
authors.lastname: Fischer
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Aditi M
authors.initials: AM
authors.lastname: Rajadhyaksha
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Mok
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Bryant
authors.initials: B
authors.lastname: Rizzo
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Rice
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Kamalpreet
authors.initials: K
authors.lastname: Singh
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kristie T
authors.initials: KT
authors.lastname: Ota
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Gerhard
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.|Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Kathryn C
authors.initials: KC
authors.lastname: Schierberl
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Glass
authors.affiliation: Laboratory of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.|Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
authors.forename: Anjali M
authors.initials: AM
authors.lastname: Rajadhyaksha
mesh_terms: D059445:Anhedonia / Q000502:physiology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D003866:Depressive Disorder / Q000378:metabolism* / Q000473:pathology; D019422:Dietary Sucrose; D004195:Disease Models, Animal; D005247:Feeding Behavior / Q000502:physiology; D000071316:Forkhead Box Protein O3 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; C469992:Ddit4 protein, mouse; D019422:Dietary Sucrose; D000071316:Forkhead Box Protein O3; C474033:FoxO3 protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases