AN INVESTIGATION OF INHIBITORY SIGNALING IN ANIMAL MODELS OF PSYCHIATRIC DISORDE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 精神分裂症是一种使人衰弱的疾病，它的许多症状包括精神病以及感觉运动门控和学习记忆的损伤。 对精神分裂症患者大脑的研究结果表明，神经递质谷氨酸的信号转导发生了微妙的变化，抑制性神经元的特定子集也减少了。这些神经元部分负责协调大量其他神经元的活动。上述数据的组合已被用来提出一个hypo-amatergic（谷氨酸信号的减少）理论作为精神分裂症的潜在原因。 该模型提出，一组特定的抑制性神经元上的兴奋性驱动（谷氨酸）的减少阻止了它们调节大脑中的其他回路，这引起了精神分裂症的症状。 来自人群和动物模型系统的其他数据已经确定，阻断NMDA谷氨酸受体的药物产生的行为变化与精神分裂症人群中观察到的一致。虽然操纵的NMDA功能已被可靠地用于精神分裂症模型（在我们的手和其他人），几乎没有数据的改变，在下游的结合位点，从这些抑制性神经元提出失调。 所提出的实验的目的是仔细检查是否抑制信号的直接改变产生类似的缺陷和/或能够修改精神分裂症的动物模型中的慢性NMDA受体阻断产生的行为和细胞改变。 初步收集的数据表明，新的行为改变符合精神分裂症。 在这些实验中，我们将检查与精神分裂症相关的行为以及在患者群体中观察到的组织变化。 在体内模型中检测与NMDA受体阻断或抑制性音调相关的行为缺陷或细胞变化的任何变化将有助于我们对精神分裂症相关机制的理解。 这些数据也可能指向一种治疗精神分裂症的新方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Schizophrenia is a debilitating disorder that's many symptoms include psychosis as well as impairments in sensory motor gating and learning and memory. Findings from studies of the brains of schizophrenic patients have indicated subtle changes in the signaling of the neurotransmitter glutamate as well as reductions in a specific sub-set of inhibitory neurons. These neurons are in part responsible for coordinating the activity of large populations of other neurons. The combination of the above data has been used to propose a hypo-glutamatergic (reduction in glutamate signaling) theory as a potential cause of schizophrenia. This model proposes that a reduction in the excitatory drive (by glutamate) on a specific group of inhibitory neurons prevents them from regulating other circuits in the brain, which gives rise to the symptoms of schizophrenia. Additional data from human populations and animal model systems have established that drugs that block the NMDA glutamate receptor produces behavioral changes consistent with what is seen in schizophrenia populations. While the manipulation of NMDA function has reliably been used to model schizophrenia (in our hands and others), there is virtually no data on alterations in the down stream binding sites from these inhibitory neurons which are proposed to be dysregulated. The goal of the proposed experiments is to carefully examine if direct alterations of inhibitory signaling produce similar deficits and/or are capable of modifying the behavioral and cellular alterations produced by chronic NMDA receptor blockade in an animal model of schizophrenia. Preliminary data collected suggest novel alterations in behavior consistent with schizophrenia. In these experiments we will examine behavior relevant to schizophrenia as well as tissue for alterations observed in patient populations. The detection of any change in either the behavioral deficits or cellular changes associated with NMDA receptor blockade or inhibitory tone in an in-vivo model would contribute a great deal to our understanding of mechanisms involved in schizophrenia. The data may also point toward a novel therapeutic approach to the treatment of schizophrenia.