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

Dedic, N.; Poehlmann, 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.

doi:10.1038/mp.2017.133

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

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

MPS-Authors

/persons/resource/persons80298

Dedic, N.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons135519

Poehlmann, M. L.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons185865

Richter, J. S.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80438

Mehta, D.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
external;

/persons/resource/persons146727

Metzger, M. W.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80306

Dine, J.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons173111

Bedenk, B. T.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80354

Hartmann, J.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80573

Wagner, K. V.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80598

Wotjak, C. T.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80315

Eder, M.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons129892

Chen, A.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;
external;

/persons/resource/persons80514

Schmidt, M. V.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

/persons/resource/persons80272

Binder, E. B.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;
external;

/persons/resource/persons80301

Deussing, J. M.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

mp2017133.pdf
(Publisher version), 768KB

Supplementary Material (public)

There is no public supplementary material available

Citation

Dedic, N., Poehlmann, M. L., Richter, J. S., Mehta, D., Czamara, D., Metzger, M. W., et al. (2018). Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood. MOLECULAR PSYCHIATRY, 23(3), 533-543. doi:10.1038/mp.2017.133.

Cite as: https://hdl.handle.net/21.11116/0000-0001-8BFF-4

Abstract

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.