NMDA Receptors and GABA neurons in schizophrenia

描述（由申请人提供）：精神分裂症是最严重的精神疾病之一，影响全球约1%的人口。最近的研究一直证明，神经认知缺陷是这种疾病的普遍特征。此外，他们越来越多地被认为是精神分裂症患者长期功能结局的最重要决定因素。不幸的是，目前所有可用的抗精神病药物在治疗这些缺陷方面的疗效充其量是中等的。这些缺陷的成功治疗将深刻影响精神分裂症的病程和患有这种疾病的患者的生活质量。 在精神分裂症中观察到的许多神经认知缺陷，如工作记忆和执行功能障碍，反映了前额叶皮层（PFC）的信息处理障碍。PFC中的信息处理受到γ-氨基丁酸（GABA）能局部回路神经元的调节。重要的是，这些后者神经元的活动也受到神经元能输入的调节。因此，GABA能局部回路神经元的直接干扰或这些神经元的异常GABA能调制可能有助于精神分裂症大脑皮层的信息处理缺陷。在这两种情况下，可以想象，信息处理缺陷可能是功能正常化的GABA神经回路的神经递质调节活动的校准。尽管这一潜在的重要的治疗意义，目前，相对知之甚少的性质GABA神经回路的PFC精神分裂症。在拟议的研究中，将使用双重原位杂交技术，在同一实验中结合使用放射性和非放射性核糖核酸探针，通过检测NMDA NR 1、NR 2A或NR 2B谷氨酸受体亚基的mRNA表达来开始探索这一重要问题，这些亚基都与精神分裂症的病理生理学有关，在精神分裂症PFC中含有GABA合成酶谷氨酸脱羧酶（GAD）67 mRNA的GABA能局部回路神经元中。

DESCRIPTION (provided by applicant): Schizophrenia is one of the most severe psychiatric disorders, affecting about 1% of the population worldwide. Recent research has consistently documented that neurocognitive deficits are pervasive features of this illness. Furthermore, they are increasingly recognized as the most important determinants of long-term functional outcome of patients suffering from schizophrenia. Unfortunately, the efficacy of all of the currently available antipsychotic medications in the treatment of these deficits is modest at best. Successful treatment of these deficits would profoundly impact the course of schizophrenia and the quality of life of patients suffering from this illness. Many of the neurocognitive deficits observed in schizophrenia, such as working memory and executive functioning impairments, reflect disturbances of information processing in the prefrontal cortex (PFC). Information processing in the PFC is modulated by gamma-aminobutyric acid (GABA) ergic local circuit neurons. Importantly, activities of these latter neurons are also regulated by glutamatergic inputs. Therefore, either direct disturbances of GABAergic local circuit neurons or abnormal glutamatergic modulation of these neurons could contribute to information processing deficits in the cerebral cortex in schizophrenia. In either scenario, it is conceivable that information processing deficits could potentially be functionally normalized by pharmacologically calibrating the activities of glutamatergic modulation of GABA neural circuitry. In spite of this potentially important therapeutic implication, currently, relatively little is known about the nature of glutamatergic modulation of GABA neural circuitry in the PFC in schizophrenia. In the proposed studies, a double in situ hybridization technique, combining the use of radioactive and non-radioactive riboprobes in the same experiment, will be used to begin to explore this important issue by examining the expression of the mRNA for the NMDA NR1, NR2A, or NR2B glutamate receptor subunits, which have all been implicated in the pathophysiology of schizophrenia, in GABAergic local circuit neurons that contain the GABA synthesizing enzyme glutamic acid decarboxylase (GAD)67 mRNA in the PFC in schizophrenia.