Altered Inhibitory Prefrontal Circuitry in Schizophrenia

描述：(申请人提供) GABA神经元的紊乱，特别是枝形吊灯细胞，似乎在 前额叶皮质(PFC)环路功能障碍在脑损伤中的重要作用 精神分裂症。然而，目前尚不清楚枝形吊灯神经元的变化是否 导致对突触后靶点的抑制性输入减少，轴突 锥体神经元的起始节(AIS)。此外，这些机制 PPC GABA神经元中的起始干扰是未知的。有趣的是，有几个 丘脑内侧背核(约TN)异常的研究报告 PFC的兴奋性输入的主要来源。然而，目前还不清楚 减少MDTN输入会导致PFC GABA神经元的变化，类似于 在精神分裂症患者中观察到。因此，在研究1中，我们将确定 枝形吊灯神经元轴突终末的突触前改变与 视交叉神经元突触后GABA受体免疫反应性的变化 在精神分裂症的一把手中使用人工智能。在PFC区域46中来自匹配的配对 精神分裂症患者和正常对照组AIS免疫反应的相对密度 对于α-2，3亚基将使用系统的、随机的 取样。我们还将阻止是否有任何变化是 精神分裂症的诊断，或与抗精神病药物治疗有关的研究 患有严重抑郁症的受试者，其中一些人曾接受精神病治疗。在……里面 研究2，我们将确定MDTN的细胞损害是否会导致 非人灵长类PFC中GABA标志物的变化 MDTN和PFC的特征与人类相似。三个月后 生存期，我们将量化PFC基因表达的任何变化 使用原位杂交和颗粒计数技术的GABA标记。

DESCRIPTION :(provided by the applicant) Disturbances in GABA neurons, particularly chandelier cells, appear to play a prominent role in the dysfunction of prefrontal cortical (PFC) circuitry in schizophrenia. However, it is unclear whether alterations in chandelier neurons result in decreased inhibitory input to their postsynaptic targets, the axon initial segments (AIS) of pyramidal neurons. Furthermore, the mechanisms that initiate disturbances in PPC GABA neurons are unknown. Interestingly, several studies report abnormalities in the mediodorsal thalamic nucleus ( about)TN), a major source of excitatory input to the PFC. However, it is unknown whether reduced MDTN input produces alterations in PFC GABA neurons similar to those observed in schizophrenia. Consequently, in Study 1, we will determine whether presynaptic alterations in chandelier neuron axon terminals are associated with postsynaptic changes in GABA receptor irnmunoreactivity in pyrarnidal neuron AIS in the PFC in schizophrenia. In PFC area 46 from matched pairs of schizophrenic and control subjects, the relative density of AIS immunoreactive for the alpha-2,3 subunits will be determined using systematic, random sampling. We will also deterrnine whether any changes are unique to the diagnosis of schizophrenia, or related to antipsychotic treatment, by studying subjects with major depression, some of whom were treated for psychosis. In Study 2, we will determine whether cellular lesions of the MDTN result in changes in GABA markers in the PFC of nonhuman primates, in whom the anatomical characteristics of the MDTN and PFC are similar to humans. After a 3 month survival period, we will quantify any changes in the mRNA expression of PFC GABA markers using in situ hybridization and grain counting techniques.