NMDA Receptor Hypofunction in the Amygdala of Schizophrenia Patients

越来越多的证据表明，精神分裂症的阴性症状可能是由杏仁核回路活动的改变介导的；特别是基底外侧杏仁核(BLA) -伏隔核（NA）和BLA-中央核（CeA）的连接。鉴于神经回路活动受突触强度/可塑性控制，NMDA受体功能作为突触可塑性的关键调节因子，可能在BLA-NA和BLA-CeA回路中发挥关键作用。NMDA受体功能与一系列神经认知功能有关，当特定脑区受到干扰时，可以诱导精神分裂症的内表型行为。我们推测，与BLA- na和BLA- CeA回路中NMDA受体功能失调相关的突触连通性改变可能导致精神分裂症的阴性症状。BLA回路接受来自前额叶皮层和纹状体的Dl和D2R介导的输入，其整体活动受到插入岛gaba能神经元的前馈和反馈抑制的调节。因此，对多巴胺能和NMDA受体信号的细胞类型特异性评估可以揭示导致精神分裂症患者杏仁核电路故障的细胞间动力学。为了解决这个问题，我们提出了一项死后研究，在该研究中，我们以细胞类型特异性的方式对NMDA和多巴胺能受体的突触强度和信号活性进行组织学和生化评估。在30名精神分裂症受试者的死后杏仁核及其匹配的对照中，我们将分别检查树突棘密度和主神经元和中间神经元突触的完整性。对死后大脑中受体信号的评估一直是一项具有挑战性的任务。我们最近开发了许多允许我们这样做的范例，并发现NMDAR2A/2B酪氨酸磷酸化的衰减降低了Src活性，并改变了SCZ患者PFC中NMDA受体复合物的蛋白质相互作用。在这个项目中，我们将使用免疫沉淀- srm -质谱分析来检测NMDA受体的功能。多巴胺能信号传导可以影响主神经元和中间神经元的NMDA受体信号传导，调节整个神经回路的活动。我们将使用组织学和生化评估来检查多巴胺能输入的突触前和突触后片段。

Accumulating evidence suggests that negative symptoms of schizophrenia may be mediated by altered circuit activity in the amygdala; specifically the basolateral amygdala (BLA) -nucleus accumbens (NA) and BLA- central nucleus (CeA) connections. Given that circuit activity is governed by synaptic strength/plasticity, NMDA receptor function, a key modulator of synaptic plasticity, may play a pivotal role in the BLA-NA and BLA-CeA circuitry. NMDA receptor function is linked to an array of neurocognitive functions and can induce endophenotypic behaviors of schizophrenia when perturbed in specific brain regions. We postulate that altered synaptic connectivity associated with dysregulated NMDA receptor function in the BLA-NA and BLA- CeA circuitry may lead to negative symptoms of schizophrenia. The BLA circuitry receives robust Dl and D2R mediated input from the prefrontal cortex and striatum and its overall activity is regulated by feedfoward and feedback inhibition via GABAergic neurons in intercalated islands. Cell type specific assessment of dopaminergic and NMDA receptor signaling therefore can reveal the intercellular dynamics leading to faulty circuitry of the amygdala in schizophrenia. To address this, we propose a postmortem study in which we conduct histologic and biochemical assessment of the synaptic strength and signaling activity of NMDA and dopaminergic receptors in a cell type specific manner. In the postmortem amygdala of 30 schizophrenia subjects and their matched controls, we will examine dendritic spine density and the integrity of synapses in principal and interneurons separately. Evaluation of receptor signaling in postmortem brains has been a challenging task. We have recently developed a number of paradigms that permit us to do so and found attenuation in tyrosine phosphorylation of NMDAR2A/2B reduced Src activity and altered protein interactions of NMDA receptor complexes in the PFC of SCZ patients. In this project we will examine the NMDA receptor function using immunoprecipitation -SRM-Mass spec analysis. Dopaminergic signaling can impact on NMDA receptor signaling in principal and interneurons modulating the overall circuit activity. We will examine presynaptic and postsynaptic segments of dopaminergic input using histologic and biochemical assessment.