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Dedic, N.* ; Pöhlmann, M.L.* ; Richter, J.S.* ; Mehta, D.* ; Czamara, D.* ; Metzger, M.W.* ; Dine, J.* ; Bedenk, B.T.* ; Hartmann, J.* ; Wagner, K.V.* ; Jurik, A.* ; Almli, L.M.* ; Lori, A.* ; Moosmang, S.* ; Hofmann, F.* ; Wotjak, C.T.* ; Rammes, G.* ; Eder, M.* ; Chen, A.* ; Ressler, K.J.* ; Wurst, W. ; Schmidt, M.V.* ; Binder, E.B.* ; Deussing, J.M.*

Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood.

Mol. Psychiatry 23, 533-543 (2018)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Single-nucleotide polymorphisms (SNPs) in CACNA1C, the a1C subunit of the voltage-gated L-type calcium channel Ca(v)1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Ca(v)1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene x environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Ca(v)1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Ca(v)1.2 in neuropsychiatric disorders with developmental and/or stressrelated origins.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Gated Calcium-channels; Posttraumatic-stress-disorder; Ca(v)1.2 Ca2+ Channels; Long-term Potentiation; Bipolar Disorder; Synaptic Plasticity; Brain-function; Neuropsychiatric Disorders; Cognitive Decline; Conditioned Fear
Sprache englisch
Veröffentlichungsjahr 2018
Prepublished im Jahr 2017
HGF-Berichtsjahr 2017
ISSN (print) / ISBN 1359-4184
e-ISSN 1476-5578
Zeitschrift Molecular Psychiatry
Quellenangaben Band: 23, Heft: 3, Seiten: 533-543 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
POF Topic(s) 30204 - Cell Programming and Repair
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500500-001
DOI 10.1038/mp.2017.133
WOS ID WOS:000425588100009
Scopus ID 85042219710
PubMed ID 28696432
Erfassungsdatum 2017-07-31
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