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The CACNA1C risk allele rs1006737 is associated with age-related prefrontal cortical thinning in bipolar I disorder.

ABSTRACT: Calcium channels control the inflow of calcium ions into cells and are involved in diverse cellular functions. The CACNA1C gene polymorphism rs1006737 A allele has been strongly associated with increased risk for bipolar disorder (BD) and with modulation of brain morphology. The medial prefrontal cortex (mPFC) has been widely associated with mood regulation in BD, but the role of this CACNA1C polymorphism in mPFC morphology and brain aging has yet to be elucidated. One hundred seventeen euthymic BD type I subjects were genotyped for CACNA1C rs1006737 and underwent 3?T three-dimensional structural magnetic resonance imaging scans to determine cortical thickness of mPFC components (superior frontal cortex (sFC), medial orbitofrontal cortex (mOFC), caudal anterior cingulate cortex (cACC) and rostral anterior cingulate cortex (rACC)). Carriers of the CACNA1C allele A exhibited greater left mOFC thickness compared to non-carriers. Moreover, CACNA1C A carriers showed age-related cortical thinning of the left cACC, whereas among A non-carriers there was not an effect of age on left cACC cortical thinning. In the sFC, mOFC and rACC (left or right), a negative correlation was observed between age and cortical thickness, regardless of CACNA1C rs1006737 A status. Further studies investigating the direct link between cortical thickness, calcium channel function, apoptosis mechanism and their underlying relationship with aging-associated cognitive decline in BD are warranted.

SUBMITTER: Soeiro-de-Souza MG

PROVIDER: S-EPMC5416698 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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The CACNA1C risk allele rs1006737 is associated with age-related prefrontal cortical thinning in bipolar I disorder.

Soeiro-de-Souza M G MG Lafer B B Moreno R A RA Nery F G FG Chile T T Chaim K K da Costa Leite C C Machado-Vieira R R Otaduy M C G MC Vallada H H

Translational psychiatry 20170411 4

Calcium channels control the inflow of calcium ions into cells and are involved in diverse cellular functions. The CACNA1C gene polymorphism rs1006737 A allele has been strongly associated with increased risk for bipolar disorder (BD) and with modulation of brain morphology. The medial prefrontal cortex (mPFC) has been widely associated with mood regulation in BD, but the role of this CACNA1C polymorphism in mPFC morphology and brain aging has yet to be elucidated. One hundred seventeen euthymic ...[more]

PMID: 28398341

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Project description:Prior studies have demonstrated reduced dendritic spine density in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia. However, it remains unclear how generalizable this finding is in schizophrenia and if it is seen in bipolar disorder, a historically distinct psychiatric condition.To assess whether spine loss is present in the DLPFC of individuals with schizophrenia and individuals with bipolar disorder.This study used postmortem human brain tissue from individuals with schizophrenia (n=14), individuals with bipolar disorder (n=9), and unaffected control participants (n=19). Tissue samples containing the DLPFC (Brodmann area 46) were Golgi-stained, and basilar dendrites of pyramidal cells in the deep half of layer III were reconstructed.The number of spines per dendrite, spine density, and dendrite length were compared across groups. We also assessed for the potential effects of clinical and demographic variables on dendritic parameters.The mean (SD) spine density was significantly reduced (ie, by 10.5%) in individuals with bipolar disorder (0.28 [0.04] spines/?m) compared with control participants (0.31 [0.05] spines/?m) (P=.02). In individuals with schizophrenia, the mean (SD) spine density was also reduced (by 6.5%; 0.29 [0.03] spines/?m) but just missed significance when compared with control participants (P=.06). There was a significant reduction in the mean (SD) number of spines per dendrite in both individuals with schizophrenia (72.8 [24.9] spines per dendrite) and individuals with bipolar disorder (68.9 [12.9] spines per dendrite) compared with controls (92.8 [31.1] spines per dendrite) (individuals with schizophrenia vs controls: 21.6% reduction [P=.003]; individuals with bipolar disorder vs controls: 25.8% reduction [P=.005]). In addition, both individuals with schizophrenia and individuals with bipolar disorder had a reduced mean (SD) dendrite length (246.5 [67.4] and 245.6 [29.8] ?m, respectively) compared with controls (301.8 [75.1] ?m) (individuals with schizophrenia vs controls: 18.3% reduction [P=.005]; individuals with bipolar disorder vs controls: 18.6% reduction [P=.005]).Dendritic spine loss in the DLPFC was seen in both individuals with schizophrenia and individuals with bipolar disorder, suggesting that the 2 disorders may share some common pathophysiological features.

Project description:Studies of head size and brain volume in autism spectrum disorders have suggested that early cortical overgrowth may be followed by prematurely arrested growth. However, the few investigations quantifying cortical thickness have yielded inconsistent results, probably due to variable ages and/or small sample sizes. We assessed differences in cortical thickness between high-functioning adolescent and young adult males with autism spectrum disorders (n = 41) and matched typically developing males (n = 40). We hypothesized thinner cortex, particularly in frontal, parietal and temporal regions, for individuals with autism spectrum disorders in comparison with typically developing controls. Furthermore, we expected to find an age × diagnosis interaction: with increasing age, more pronounced cortical thinning would be observed in autism spectrum disorders than typically developing participants. T(1)-weighted magnetization prepared rapid gradient echo 3 T magnetic resonance imaging scans were acquired from high-functioning males with autism spectrum disorders and from typically developing males matched group-wise on age (range 12-24 years), intelligence quotient (≥ 85) and handedness. Both gyral-level and vertex-based analyses revealed significantly thinner cortex in the autism spectrum disorders group that was located predominantly in left temporal and parietal regions (i.e. the superior temporal sulcus, inferior temporal, postcentral/superior parietal and supramarginal gyri). These findings remained largely unchanged after controlling for intelligence quotient and after accounting for psychotropic medication usage and comorbid psychopathology. Furthermore, a significant age × diagnosis interaction was found in the left fusiform/inferior temporal cortex: participants with autism spectrum disorders had thinner cortex in this region with increasing age to a greater degree than did typically developing participants. Follow-up within group comparisons revealed significant age-related thinning in the autism spectrum disorders group but not in the typically developing group. Both thinner temporal and parietal cortices during adolescence and young adulthood and discrepantly accelerated age-related cortical thinning in autism spectrum disorders suggest that a second period of abnormal cortical growth (i.e. greater thinning) may be characteristic of these disorders.

Dataset Information

The CACNA1C risk allele rs1006737 is associated with age-related prefrontal cortical thinning in bipolar I disorder.

Publications

The CACNA1C risk allele rs1006737 is associated with age-related prefrontal cortical thinning in bipolar I disorder.

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