Molecular Basis of Deviance Detection and Stimulus Encoding

精神分裂症的认知缺陷以及阳性和阴性症状可能是由异常引起的。 在适当的神经电路中检测和编码刺激的非常基本的过程中。这些过程 可通过事件相关电位(ERPs)、脑电振荡和fMRI激活进行监测。异常 在精神分裂症患者中，在多个听觉皮层事件相关电位中以及在theta和Gamma中都有反复报道 与异常和新奇检测相关的脑电节律以及与编码和提取 情节记忆和工作记忆。如子项目0001和0003所述，我们的CCNMD发现在精神分裂症患者中 伽马振荡异常与异常的fMRI大胆反应相关，包括那些在上级 颞回和海马体。在大脑皮层和大脑皮层产生伽马和西塔节律的微电路 近些年来，海马体已被阐明。在这两个大脑区域，微电路是相似的 由与一种或多种类型的GABA能相互连接的谷氨酸能投射神经元组成 中间神经元。我们认为在精神分裂症中，谷氨酸能向GABA能的输入功能减退 中间神经元出现在theta和Gamma微电路中，从而导致GABA能功能减退 电路中的异常振荡。 我们的研究已经确定了精神分裂症中可能导致谷氨酸和GABA能的因素 海马区和皮质脑区功能障碍，包括异常的dybindin表达和 N-甲基-D-天冬氨酸受体异常激活和神经调节蛋白1-ERBB4信号通路。子项目0007将测试 与这些发现相关的假说和谷氨酸-氨基丁酸能的潜在后果 神经传递。目标1将检查突触前因子是否对谷氨酸能起作用 精神分裂症和异常结合基因突变小鼠的Theta和Gamma微电路功能异常 (桑迪)。目标2将在人类死后组织和GSA中使用一种新的神经化学刺激范式 高表达小鼠以检测NMDA受体功能和NMDAR-多巴胺受体相互作用 可能与精神分裂症患者的Theta和Gamma微回路功能障碍有关。目标3将考察 事实上，GABA能传递的标志物在该疾病的伽马和西塔微回路中发生了改变。

Cognitive deficits as well as positive and negative symptoms in schizophrenia may arise from abnormalities in very basic processes of detecting and encoding stimuli in appropriate neural circuitry. Those processes can be monitored with event-related potentials (ERPs), EEG oscillations and fMRI activation. Abnormalities have been reported repeatedly in schizophrenia in multiple auditory cortical ERPs and in theta and gamma EEG rhythms associated with deviance and novelty detection, as well as with encoding and retrieval of episodic and working memory. As described in Subprojects 0001 and 0003, our CCNMD has found that in schizophrenia gamma oscillatory abnormalities correlate with abnormal fMRI BOLD responses, including those in superior temporal gyrus and hippocampus. The microcircuits generating gamma and theta rhythms in neocortex and hippocampus have been elucidated in recent years. In both brain regions, the microcircuits are similar and consist of glutamatergic projection neurons reciprocally connected with one or more types of GABAergic interneurons. We propose that in schizophrenia hypofunction of glutamatergic input to GABAergic interneurons occurs in theta and gamma microcircuits with consequent GABAergic hypofunction leading to abnormal oscillations in the circuits. Our studies have identified factors in schizophrenia that could lead to glutamatergic and GABAergic dysfunction in hippocampal and cortical brain regions, including abnormal dysbindin expression and abnormal activation of NMDA receptors and the neuregulin 1-erbB4 signaling pathway. Subproject 0007 will test hypotheses related to these findings and potential consequences for glutamatergic-GABAergic neurotransmission. Aim 1 will examine whether or not presynaptic factors that contribute to glutamatergic function of theta and gamma microcircuits are abnormal in schizophrenia and a dysbindin mutant mouse (sandy). Aim 2 will use a novel neurochemical stimulation paradigm in human postmortem tissue and a Gsa overexpressing mouse to examine NMDA receptor function and NMDAR-dopamine receptor interactions that may contribute to theta and gamma microcircuit dysfunction in schizophrenia. Aim 3 will examine whether markers of GABAergic transmission are in fact altered in the gamma and theta microcircuits in that disorder.