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. 2010 Nov 1;68(9):801-10.
doi: 10.1016/j.biopsych.2010.06.019. Epub 2010 Aug 17.

Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans

David T Dao  1 , Pamela Belmonte Mahon, Xiang Cai, Colleen E Kovacsics, Robert A Blackwell, Michal Arad, Jianxin Shi, Peter P Zandi, Patricio O'Donnell; Bipolar Genome Study (BiGS) Consortium; James A Knowles, Myrna M Weissman, William Coryell, William A Scheftner, William B Lawson, Douglas F Levinson, Scott M Thompson, James B Potash, Todd D Gould
Affiliations

Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans

David T Dao et al. Biol Psychiatry. .

Abstract

Background: Recent genome-wide association studies have associated polymorphisms in the gene CACNA1C, which codes for Ca(v)1.2, 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; p(corrected) = .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.

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Figures

Figure 1
Figure 1. Effect of Cacna1c HET knockout on activity and exploration
(a) Male HET mice did not differ significantly from WT mice in open field locomotion. (b) In females, genotype had a significant effect on locomotion in the open field (P<0.05). Neither Male (c) nor Female (d) HET mice were significantly different than WT mice in homecage activity. (e) Male and (f) female HET mice had lower exploratory activity on the holeboard test. Data are expressed as mean ± SEM. *, P≤0.05.
Figure 2
Figure 2. Effect of Cacna1c HET knockout on risk-taking and anxiety-like behavior
(a) Male HET mice had no significant difference in center time in a large open field. (b) Female HET mice spent less time in the center of a large open field. (c) There was no significant difference in time spent on the open arms of the elevated plus maze in male HET mice. (d) Female HET mice spent less time on the open arms of the elevated plus maze. (e) There was no significant difference in the time male HET mice spent in the light compartment of the light-dark box. (f) Female HET mice spent less time in the light compartment of the light-dark box. There was no significant effect of genotype in either (g) male or (h) female to modify latency to drink in the novel cage when compared to WT mice. There was no significant effect of genotype in either (i) male or (j) female subjects to modify hyperthermia in response to stress. Data are expressed as mean ± SEM. *, P≤0.05; ***, P<0.001.
Figure 3
Figure 3. Effect of Cacna1c HET knockout on response to d-amphetamine and acoustic startle response
(a) Male WT and HET mice habituated at the same level of locomotion during saline injection days 1–7. There was a significant effect of genotype to modify sensitization to d-amphetamine over days 8–12 in male mice (P<0.05). In males there was a trend for an effect of genotype to modify long-term sensitization to d-amphetamine on day 39 (P=0.063) but not day 18. (b) Female HET mice had lower locomotion during the saline habituation phase days 1–6 (P<0.001). In female HET mice there was a significant effect of genotype on sensitization to d-amphetamine (P<0.001). There remained a significant effect of genotype when females were re-challenged with d-amphetamine sensitization days 18 and 39 (P<0.001). (c) Male HET mice had no significant difference in response to multiple acoustic startle intensities. (d) Female HET mice had significantly lower acoustic startle response at 120dB. Data are expressed as mean ± SEM. *, P≤0.05 Bonferroni posttest.
Figure 4
Figure 4. Effect of Cacna1c HET knockout in tests of antidepressant efficacy
(a) Male HET mice spent significantly less time immobile on the forced swim test (FST) (b) Female HET mice spent significantly less time immobile on the FST. (c) Male HET mice spent significantly less time immobile in the tail suspension test (TST) (d) Female HET mice spent significantly less time immobile in the TST. Data are expressed as mean ± SEM. *, P≤0.05 **, P<0.01.
Figure 5
Figure 5. Effect of Cacna1c HET knockout on depression-like behavior in the learned helplessness model
Mice were tested one and seven days after induction of learned helplessness with 0.3 mA inescapable shocks. In trials P1–P5, shock start and gate opening was simultaneous. In trials 1–25, a delay of three seconds was imposed between shock start and gate opening. In male mice on days 1 (a) and 7 (c), there was no significant effect of genotype in trials P1–P5, and in trials 1–25. In female mice on days 1 (b) and 7 (d), there were no significant differences in performance in trials P1–P5, but there was a significant effect of genotype in trials 1–25 (P<0.05). Data are expressed as mean ± SEM.
Figure 6
Figure 6. Two human intronic CACNA1C single nucleotide polymorphisms (SNPs) show sex-specific association with mood disorders
(a) CACNA1C is a 644.7 kb gene located on chromosome 12 at 2,032,677 bp to 2,677,376 bp (hg18). rs2340419 and rs2370411 are located within intron 3, which is 329 kb long. They are 142 kb from each other. rs1006737, the most significant result in a prior BP GWAS meta-analysis (10), is also in intron 3, located between rs2370411 and rs2370419. (b) Results by study for rs2370419. NIMH-BP: female odds ratio 1.69, male odds ratio, 0.95. GenRED-MDD: female odds ratio 1.56, male odds ratio 0.65. Both studies showed nominally significant p-values for the interaction of sex and diagnosis. Controls were non-overlapping. (c) Results by study for rs2370411. NIMH-BP: female odds ratio 1.20, male odds ratio, 0.81. GenRED-MDD: female odds ratio 1.45, male odds ratio 0.93. Both studies showed nominally significant p-values for the interaction of sex and diagnosis. Controls were non-overlapping.
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