title: The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons.
abstract: Genetic variations in CACNA1C, which encodes the Cav1.2 subunit of L-type calcium channels (LTCCs), are associated with multiple forms of neuropsychiatric disease that manifest high anxiety in patients. In parallel, mice harboring forebrain-specific conditional knockout of cacna1c (forebrain-Cav1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Cav1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Cav1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Cav1.2 cKO mice exhibit enhanced cell death of young hippocampal neurons, with no change in NPC proliferation, hippocampal size, dentate gyrus thickness, or corticosterone levels compared with wild-type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinase-mediated knockdown of adult hippocampal Cav1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Cav1.2 cKO mice with the neuroprotective agent P7C3-A20 restored the net magnitude of postnatal hippocampal neurogenesis to wild-type levels without ameliorating their deficit in BDNF expression. The role of Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C. Visual Abstract.
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, New York 10065; Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, Cornell University, New York, New York 10065.
authors.forename: Anni S
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Neuroscience Graduate Program, UT Southwestern Medical Center, Dallas, Texas 75390; Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242.
authors.forename: Héctor
authors.identifier: 0000-0001-6983-6963
authors.initials: H
authors.lastname: De Jesús-Cortés
authors.affiliation: Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine , Cornell University, New York, New York 10065.
authors.forename: Zeeba D
authors.initials: ZD
authors.lastname: Kabir
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center , Dallas, Texas 75390.
authors.forename: Whitney
authors.initials: W
authors.lastname: Knobbe
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center , Dallas, Texas 75390.
authors.forename: Madeline
authors.initials: M
authors.lastname: Orr
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, New York 10065; Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, Cornell University, New York, New York 10065.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Burgdorf
authors.affiliation: Department of Psychiatry, UT Southwestern Medical Center , Dallas, Texas 75390.
authors.forename: Paula
authors.initials: P
authors.lastname: Huntington
authors.affiliation: Department of Psychiatry, University of Iowa , Carver College of Medicine , Iowa City, Iowa 52242.
authors.forename: Latisha
authors.initials: L
authors.lastname: McDaniel
authors.affiliation: Department of Psychiatry, University of Iowa , Carver College of Medicine , Iowa City, Iowa 52242.
authors.forename: Jeremiah K
authors.initials: JK
authors.lastname: Britt
authors.affiliation: Institute of Pharmacology, Technical University Munich, Munich, Germany; Research Group 923, Technical University Munich, Munich, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Hoffmann
authors.affiliation: Pathology and Laboratory Medicine, Emory University School of Medicine , Atlanta, Georgia 30322.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
authors.affiliation: Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, New York 10065; Division of Pediatric Neurology, Department of Pediatrics, Weill Cornell Medicine, Cornell University, New York, New York 10065; Weill Cornell Autism Research Program, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Anjali M
authors.initials: AM
authors.lastname: Rajadhyaksha
authors.affiliation: Department of Psychiatry, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242; Weill Cornell Autism Research Program, Weill Cornell Medical College, New York, New York 10065; Department of Neurology, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242; Department of Free Radical and Radiation Biology Program, Department of Radiation Oncology Holden Comprehensive Cancer Center, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242; Department of Veteran Affairs, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Pieper
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D002470:Cell Survival / Q000235:genetics; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D006624:Hippocampus / Q000166:cytology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D016548:Prosencephalon / Q000166:cytology; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics / Q000473:pathology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D002227:Carbazoles; D018696:Neuroprotective Agents; C552520:P7C3 compound; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D001973:Bromodeoxyuridine; D003345:Corticosterone
keywords: Cav; P7C3; P7C3A20; anxiety; neurogenesis; neuroprotection