Altered Inhibitory Prefrontal Circuitry in Schizophrenia

精神分裂症抑制性前额叶回路的改变

• 批准号: 6607356
• 负责人: DAVID W VOLK
• 金额: $ 4.6万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6607356
• 关键词: GABA receptor; Primates; Rodentias; clinical research; experimental brain lesion; gamma aminobutyrate; human tissue; in situ hybridization; major depression; neural inhibition; neural transmission; neurochemistry; predoctoral investigator; prefrontal lobe /cortex; schizophrenia; thalamic nuclei

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.

描述：（申请人提供） GABA神经元的紊乱，尤其是枝形细胞，似乎在 前额叶皮层（PFC）电路功能障碍的突出作用， 精神分裂症然而，尚不清楚枝形吊灯神经元的改变是否 导致对突触后靶点轴突的抑制性输入减少 锥体神经元的起始段（AIS）。此外， PPC GABA神经元中起始干扰是未知的。有趣的是，几个 研究报告丘脑背内侧核异常（约TN）， 主要来源的兴奋性输入到PFC。然而，它是未知的， 减少MDTN输入产生的PFC GABA神经元的变化类似于 在精神分裂症中观察到。因此，在研究1中，我们将确定 枝形神经元轴突终末的突触前改变与 吡啶类神经元GABA受体免疫反应性的突触后变化 精神分裂症患者PFC中的AIS。在PFC区域46中， 精神分裂症和对照组，AIS免疫反应性的相对密度 对于α-2，3亚基，将使用系统、随机 取样.我们还将确定是否有任何变化是独一无二的， 精神分裂症的诊断，或与抗精神病药物治疗有关，通过研究 患有严重抑郁症的受试者，其中一些人接受了精神病治疗。在 研究2，我们将确定MDTN的细胞病变是否导致 在非人灵长类动物PFC中GABA标记物的变化，其中解剖学 MDTN和PFC的特征与人类相似。3个月后 生存期，我们将定量PFC mRNA表达的任何变化， 使用原位杂交和颗粒计数技术的GABA标记。