Altered Expression of GABAA Delta and Alpha 4 Receptor Subunits in Schizophrenia

描述（由申请人提供）：抑制性神经传递缺陷似乎在精神分裂症患者前额叶皮质（PFC）功能障碍中起着重要作用。虽然一些GABAA受体的密度上调，明显补偿了GABAA能神经传递的减少，但我们的初步数据表明，GABAA亚基sigma和alpha4的mRNA表达水平在精神分裂症中降低。含有sigma和alpha4亚基的GABAA受体介导“强直抑制”，这增加了细胞的输入电导，使其不太可能产生动作电位。因此，由这些受体介导的gaba能信号的减少可能导致PFC电路抑制调节的改变。此外，导致sigma和alpha4亚基表达缺陷的发病机制尚不清楚。研究表明，精神分裂症中gaba相关标记物的缺失与通过NMDA受体的神经传递减少有关。然而，目前尚不清楚NMDA受体信号传导减少是否会导致sigma和alpha4亚基水平下降。目的1。目的：确定精神分裂症患者PFC中sigma和alpha4亚基mRNA水平是否降低。我们将利用原位杂交和颗粒计数技术，评估这些转录本在精神分裂症和对照组配对配对的PFC中的解剖定位和表达模式。目标2。目的：确定抗精神病药物治疗是否影响sigma和alpha4亚基表达的变化。精神分裂症患者sigma和alpha4亚基水平降低的临床意义取决于这些变化是疾病过程特异性的还是抗精神病药物治疗的结果。因此，我们将使用原位杂交技术来评估长期暴露于氟哌啶醇、奥氮平或安慰剂的非人灵长类动物PFC中sigma和alpha4亚基的mRNA水平。目标3。测定NR1亚型小鼠PFC中sigma和alpha4亚基的表达水平是否降低。精神分裂症中sigma和alpha4亚基的表达减少可能代表了NMDA受体信号传导的缺陷。我们将利用原位杂交和颗粒计数技术来评估基因工程小鼠前额皮质（PFC）中sigma和alpha4亚基的mRNA水平，以表达降低的NMDA NR1亚基水平。此外，利用免疫细胞化学，我们将确定NR1亚型小鼠PFC中sigma和alpha4亚基的蛋白水平是否降低。总之，这些研究将提供对精神分裂症中抑制性神经传递缺陷的病理实体和可能产生它们的机制的理解。

DESCRIPTION (provided by applicant): Deficits in inhibitory neurotransmission appear to play a prominent role in the dysfunction of the prefrontal cortex (PFC) in schizophrenia. Although the density of some GABAA receptors is upregulated, apparently compensating for decreased GABAergic neurotransmission, our preliminary data suggest that the mRNA expression levels of the GABAA subunits sigma and alpha4 are decreased in schizophrenia. GABAA receptors containing sigma and alpha4 subunits mediate "tonic inhibition", which increases a cell's input conductance, making it less likely that an action potential is generated. Thus, decreased GABAergic signaling mediated by these receptors could contribute to altered inhibitory regulation of PFC circuitry. In addition, the pathogenetic mechanisms that cause deficits in the expression of sigma and alpha4 subunits are unknown. Studies suggest that deficits in GABA-related markers in schizophrenia are associated with reduced neurotransmission through NMDA receptors. However, it is unknown whether decreased NMDA receptor signaling results in decreased levels of sigma and alpha4 subunits. Aim 1. To determine whether the mRNA levels of sigma and alpha4 subunits are decreased in the PFC in schizophrenia. We will assess the anatomical localization and expression pattern of these transcripts across the PFC of matched pairs of schizophrenia and control subjects, using in situ hybridization and grain counting techniques. Aim 2. To determine whether changes in the expression of sigma and alpha4 subunits are influenced by treatment with antipsychotic medications. The clinical relevance of reduced levels of sigma and alpha4 subunits in schizophrenia depends on whether these changes are specific to the disease process or are a consequence of exposure to antipsychotic medication. Therefore, we will use in situ hybridization to assess the mRNA levels of sigma and alpha4 subunits in the PFC of non-human primates chronically exposed to haloperidol, olanzapine or placebo. Aim 3. To determine whether the expression levels of sigma and alpha4 subunits are decreased in the PFC of NR1 hypomorphic mice. Decreased expression of sigma and alpha4 subunits in schizophrenia may represent a deficit in signaling through NMDA receptors. We will utilize in situ hybridization and grain counting techniques to assess the mRNA levels of sigma and alpha4 subunits in the prefrontal cortex (PFC) of mice genetically engineered to express reduced levels of the NMDA NR1 subunit. In addition, using immunocytochemistry, we will determine if the protein levels of sigma and alpha4 subunits are reduced in the PFC of NR1 hypomorphic mice. Together, these studies will provide an understanding of the pathological entities that contribute to deficits in inhibitory neurotransmission in schizophrenia and the mechanisms that may give rise to them.