Elsevier

Biological Psychiatry

Volume 68, Issue 9, 1 November 2010, Pages 801-810
Biological Psychiatry

Archival Report
Mood Disorder Susceptibility Gene CACNA1C Modifies Mood-Related Behaviors in Mice and Interacts with Sex to Influence Behavior in Mice and Diagnosis in Humans

https://doi.org/10.1016/j.biopsych.2010.06.019Get rights and content

Background

Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Cav1.2, with a bipolar disorder and depression diagnosis.

Methods

The behaviors of wild-type and Cacna1c heterozygous mice of both sexes were evaluated in a number of tests. Based upon sex differences in our mouse data, we assessed a gene × sex interaction for diagnosis of mood disorders in human subjects. Data from the National Institute of Mental Health Genetics Initiative Bipolar Disorder Consortium and the Genetics of Recurrent Early-Onset Major Depression Consortium were examined using a combined dataset that included 2021 mood disorder cases (1223 female cases) and 1840 control subjects (837 female subjects).

Results

In both male and female mice, Cacna1c haploinsufficiency was associated with lower exploratory behavior, decreased response to amphetamine, and antidepressant-like behavior in the forced swim and tail suspension tests. Female, but not male, heterozygous mice displayed decreased risk-taking behavior or increased anxiety in multiple tests, greater attenuation of amphetamine-induced hyperlocomotion, decreased development of learned helplessness, and a decreased acoustic startle response, indicating a sex-specific role of Cacna1c. In humans, sex-specific genetic association was seen for two intronic single nucleotide polymorphisms, rs2370419 and rs2470411, in CACNA1C, with effects in female subjects (odds ratio = 1.64, 1.32) but not in male subjects (odds ratio = .82, .86). The interactions by sex were significant after correction for testing 190 single nucleotide polymorphisms (p = 1.4 × 10−4, 2.1 × 10−4; pcorrected = .03, .04) and were consistent across two large datasets.

Conclusions

Our preclinical results support a role for CACNA1C in mood disorder pathophysiology, and the combination of human genetic and preclinical data support an interaction between sex and genotype.

Section snippets

Animals

Founder mice were obtained from Jackson Laboratories (stock number 005783, Bar Harbor, Maine) that had been backcrossed to C57BL/6J for at least seven generations (see Supplement 1 for additional details).

Behavioral Tests

Mice were tested in the open field, home cage activity, hole board, elevated plus maze, light-dark box, novelty-induced hypophagia, stress-induced hyperthermia, sensitization to d-amphetamine, acoustic startle, and forced swim tests (FSTs) using established methods. Minor alterations to the

Baseline Behaviors, Activity, and Exploration

As homozygous deletion of Cacna1c results in embryonic lethality in mice (29), we conducted studies with heterozygous (Cacna1c+/- [HET]) Cacna1c knockout mice and compared these animals with their wild-type (Cacna1c+/+ [WT]) littermates. Western blot analysis confirmed that heterozygous knockout of Cacna1c results in a significant decrease in levels of Cav1.2 without a change in Cav1.3, which is the most likely protein to compensate for such changes (Figure S1 in Supplement 1). As expected,

Discussion

Our data indicate that in male and female mice, Cacna1c haploinsufficiency is associated with decreased exploratory behavior, decreased hyperlocomotion in response to amphetamine, and antidepressant-like behavior in the FST and TST. There are also sex differences in the effects of Cacna1c haploinsufficiency: female mice exhibit more robust attenuation of amphetamine-induced hyperlocomotion than male mice and, unlike male mice, display an attenuated acoustic startle response and reduced

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    Authors DTD and PBM and authors JBP and TDG contributed equally to this work.

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