Development of Prefrontal Inhibition and Schizophrenia

前额叶抑制和精神分裂症的发展

• 批准号: 6868780
• 负责人: David A Lewis
• 金额: $ 39.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6868780
• 关键词: Macaca mulatta; age difference; animal puberty; ankyrins; behavioral /social science research tag; biological models; calcium flux; developmental neurobiology; developmental psychology; electrophysiology; gamma aminobutyrate; in situ hybridization; intercellular connection; juvenile animal; membrane transport proteins; neural transmission; neuropathology; neuroregulation; prefrontal lobe /cortex; pyramidal cells; schizophrenia; short term memory

DESCRIPTION (provided by applicant): A subset of GABA neurons in the dorsolateral prefrontal cortex (DLPFC) is altered in subjects with schizophrenia. The affected neurons include parvalbumin (PV)-containing chandelier neurons whose axon terminals form vertical arrangements ("cartridges") that synapse exclusively on the axon initial segment (AIS) of pyramidal cells. Networks of PV-containing GABA neurons give rise to gamma band oscillations, and impairments in working memory function in schizophrenia are accompanied by reductions in DLPFC gamma band power. Thus, alterations in PV-containing chandelier neurons may play a critical role in the pathophysiology of working memory dysfunction in schizophrenia. Understanding this role requires knowledge of the normal development of chandelier neurons during adolescence, the typical age of onset of schizophrenia. In the monkey DLPFC, the densities of chandelier axon cartridges immunoreactive (IR) for PV or the GABA membrane transporter (GAT1) markedly decline during adolescence. Because reductions in PV and GAT1 increase the release and efficacy of GABA in response to repetitive stimuli, a decline during adolescence in PV and GAT1 in cartridges may substantially enhance the chandelier neuron regulation of pyramidal cell output, and contribute to the maturation of working memory performance. Thus, the proposed studies are designed to determine whether the normal maturation of monkey DLPFC chandelier neurons during adolescence strengthens their ability to regulate pyramidal cell output and to synchronize the activity of larger groups of pyramidal cells at gamma frequencies. Aims 1-3 tests the hypothesis that adolescence is associated with decreased PV and GAT1 proteins in cartridges, and Aim 4 tests the hypothesis that these changes are associated with an increased efficacy of chandelier neuron inputs to pyramidal cells under the repetitive firing present during working memory tasks. Aim 5 examines changes in chandelier cells during adolescence that may increase their ability to generate gamma oscillations, and Aim 6 tests the hypothesis that gamma band power in the DLPFC increases during adolescence. The strengths of the proposed studies include the integration of anatomical, molecular and electrophysiological techniques in a primate model system to explore the cellular and circuitry bases for the normal maturation of working memory performance and to inform the pathophysiology of working memory dysfunction in schizophrenia.

描述（由申请人提供）：在精神分裂症患者中，背外侧前额叶皮层（DLPFC）中的GABA神经元子集改变了。受影响的神经元包括含有轴突末端的载有垂直排列（“墨盒”），这些神经元仅在锥体细胞的轴突初始段（AIS）上突触。含PV的GABA神经元网络会引起伽马频带振荡，精神分裂症的工作记忆功能受损以及DLPFC伽马频段功率的减少。因此，含PV的枝形吊灯神经元的改变可能在精神分裂症的工作记忆功能障碍的病理生理学中起关键作用。了解这一作用需要了解青春期枝形吊灯神经元的正常发育，这是精神分裂症的典型年龄。在猴子DLPFC中，PV或GABA膜转运蛋白转运蛋白（GAT1）在青春期期间显着下降的枝形吊灯弹药筒（IR）的密度显着下降。由于PV和GAT1的降低增加了GABA对重复刺激的释放和功效，因此墨盒中PV和GAT1在青春期的下降可能会大大增强锥体细胞输出的枝形吊灯神经元调节，并为工作记忆力的成熟贡献。因此，拟议的研究旨在确定青春期猴子DLPFC枝形吊灯神经元的正常成熟是否可以增强其调节锥体细胞输出的能力，并同步γ频率下较大的锥体细胞的活性。 AIMS 1-3检验了以下假设：青春期与墨盒中的PV和GAT1蛋白降低有关，AIM 4检验了以下假设：这些变化与在工作记忆任务期间重复性启动下对金字塔细胞的枝形吊灯神经输入的功效增加有关。 AIM 5检查了青春期枝形吊灯细胞的变化，这可能会增加其产生γ振荡的能力，AIM 6检验了以下假设：DLPFC中的γ频带功率在青春期增加。拟议的研究的优势包括在灵长类动物模型系统中整合解剖学，分子和电生理技术，以探索用于工作记忆性能正常成熟的细胞和电路碱基，并为精神分裂症中工作记忆功能障碍的病理生理学提供病理生理学。