Shukla Abhay A, Jha Manish, Birchfield Thomas, Mukherjee Shibani, Gleason Kelly, Abdisalaam Salim, Asaithamby Aroumougame, Adams-Huet Beverley, Tamminga Carol A, Ghose Subroto
Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
Department of Radiation Oncology/Division of Molecular Radiation Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, United States.
Schizophr Res. 2016 May;173(1-2):94-100. doi: 10.1016/j.schres.2016.03.019. Epub 2016 Mar 24.
The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function. Next, we compared target gene expression profiles in a cohort of control and schizophrenia cases, each characterized by COMT genotype. We find that the COMT val allele in control subjects is associated with significant upregulation of GluN2A and GAD67 mRNA levels compared to met carriers. Comparisons between control and schizophrenia groups reveal that GluN2A, GAD67 and DRD2 are differentially regulated between diagnostic groups in a genotype specific manner. Chronic antipsychotic treatment in rodents did not explain these differences. These data demonstrate an association between COMTval158met genotype and gene expression profile in the DLPFC of controls, possibly adaptations to maintain DLPFC function. In schizophrenia val homozygotes, these adaptations are not seen and could reflect pathophysiologic mechanisms related to the known poorer performance of these subjects on DLPFC-dependent tasks.
儿茶酚-O-甲基转移酶（COMT）的单核苷酸val158met多态性会影响前额叶皮质功能。依赖于背外侧前额叶皮质（DLPFC）的工作记忆已被反复证明会受到这种COMT多态性的影响。高活性的COMT val亚型与较低的突触多巴胺水平相关。突触多巴胺水平的改变预计会导致突触内以及DLPFC神经回路内的分子适应性变化。在这项使用高质量DLPFC组织的人体尸检研究中，我们首先研究了COMT val158met多态性对多巴胺神经传递标志物、N-甲基-D-天冬氨酸（NMDA）受体亚基和谷氨酸脱羧酶67（GAD67）的影响，所有这些都已知对DLPFC神经回路和功能至关重要。接下来，我们比较了一组对照和精神分裂症病例的靶基因表达谱，每组病例均以COMT基因型为特征。我们发现，与携带met等位基因的个体相比，对照组中COMT val等位基因与GluN2A和GAD67 mRNA水平的显著上调相关。对照和精神分裂症组之间的比较显示，GluN2A、GAD67和DRD2在诊断组之间以基因型特异性方式受到不同调节。啮齿动物的慢性抗精神病药物治疗并不能解释这些差异。这些数据表明COMTval158met基因型与对照组DLPFC中的基因表达谱之间存在关联，这可能是为维持DLPFC功能而产生的适应性变化。在精神分裂症的val纯合子中，未观察到这些适应性变化，这可能反映了与这些受试者在依赖DLPFC的任务上表现较差相关的病理生理机制。
