Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
Department of Psychiatry and Psychotherapy, Philipps-University Marburg, Rudolf-Bultmann-Str. 8, 35039 Marburg, Germany.
J Psychiatr Res. 2014 Jun;53:38-46. doi: 10.1016/j.jpsychires.2014.02.003. Epub 2014 Feb 14.
Genetic studies found the A allele of the single nucleotide polymorphism rs1006737 in the CACNA1C gene, which encodes for the alpha 1C subunit of the voltage-dependent, L-type calcium ion channel Cav1.2, to be overrepresented in patients with major depressive disorder (MDD). Altered prefrontal brain functioning and impaired semantic verbal fluency (SVF) are robust findings in these patients. A recent functional magnetic resonance imaging (fMRI) study found the A allele to be associated with poorer performance and increased left inferior frontal gyrus (IFG) activation during SVF tasks in healthy subjects. In the present study, we investigated the effects of rs1006737 on neural processing during SVF in MDD. In response to semantic category cues, 40 patients with MDD and 40 matched controls overtly generated words while brain activity was measured with fMRI. As revealed by whole brain analyses, genotype significantly affected brain activity in patients. Compared to patients with GG genotype, patients with A allele demonstrated increased task-related activation in the left middle/inferior frontal gyrus and the bilateral cerebellum. Patients with A allele also showed enhanced functional coupling between left middle/inferior and right superior/middle frontal gyri. No differential effects of genotype on SVF performance or brain activation were found between diagnostic groups. The current data provide further evidence for an impact of rs1006737 on the left IFG and demonstrate that genetic variation in CACNA1C modulates neural responses in patients with MDD. The observed functional alterations in prefrontal and cerebellar areas might represent a mechanism by which rs1006737 influences susceptibility to MDD.
遗传研究发现，单核苷酸多态性 rs1006737 的 A 等位基因位于 CACNA1C 基因中，该基因编码电压依赖性 L 型钙离子通道 Cav1.2 的α1C 亚基，在重度抑郁症（MDD）患者中过度表达。这些患者的前额叶脑功能改变和语义流畅性（SVF）受损是强有力的发现。最近的一项功能磁共振成像（fMRI）研究发现，A 等位基因与健康受试者在 SVF 任务中的表现较差和左侧额下回（IFG）激活增加有关。在本研究中，我们研究了 rs1006737 对 MDD 患者 SVF 期间神经处理的影响。在语义类别线索的刺激下，40 名 MDD 患者和 40 名匹配的对照者在 fMRI 测量大脑活动的同时进行了口头生成词的任务。全脑分析结果显示，基因型对患者的大脑活动有显著影响。与 GG 基因型的患者相比，携带 A 等位基因的患者在左侧中/下回和双侧小脑的任务相关激活中表现出增加。携带 A 等位基因的患者还表现出左中/下和右上/中额回之间的功能耦合增强。在诊断组之间，基因型对 SVF 表现或大脑激活没有差异影响。目前的数据进一步证明了 rs1006737 对左侧 IFG 的影响，并表明 CACNA1C 中的遗传变异调节了 MDD 患者的神经反应。前额叶和小脑区域观察到的功能改变可能代表 rs1006737 影响 MDD 易感性的一种机制。
