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Author Notes:

Molecular Neurogenetics, Department of Stress Neurobiogy and Neurogentics, Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, Munich 80804, Germany. E-mail: deussing@psych.mpg.de

We thank Marcel Schieven for his excellent technical assistance.

We thank Günther Schütz for providing Camk2α-CreERT2 mice and Klaus-Armin Nave for providing Nex-Cre mice.

The authors declare no conflict of interest

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Research Funding:

This work was partially supported by the German Federal Ministry of Education and Research, within the framework of the e:Med research and funding concept (IntegraMent: Integrated Understanding of Causes and Mechanisms in Mental Disorders; FKZ 01ZX1314H) and by the program for medical genome research within the framework of the NGFN-Plus (FKZ: 01GS08151).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Neurosciences
  • Psychiatry
  • Neurosciences & Neurology
  • 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

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

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Journal Title:

Molecular Psychiatry

Volume:

Volume 23, Number 3

Publisher:

, Pages 533-543

Type of Work:

Article | Final Publisher PDF

Abstract:

Single-nucleotide polymorphisms (SNPs) in CACNA1C, the α1C 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 × 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 stress-related origins.

Copyright information:

© The Author(s) 2018.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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