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）：精神分裂症受试者的背外侧前额皮质（DLPFC）中的 GABA 神经元子集发生了改变。受影响的神经元包括含有小白蛋白（PV）的吊灯神经元，其轴突末端形成垂直排列（“盒”），仅在锥体细胞的轴突初始段（AIS）上突触。含有 PV 的 GABA 神经元网络会引起伽马带振荡，精神分裂症患者工作记忆功能的损害会伴随着 DLPFC 伽马带功率的降低。因此，含有PV的吊灯神经元的改变可能在精神分裂症工作记忆功能障碍的病理生理学中发挥关键作用。要理解这一作用，需要了解青春期（精神分裂症的典型发病年龄）吊灯神经元的正常发育。在猴子 DLPFC 中，PV 或 GABA 膜转运蛋白 (GAT1) 免疫反应 (IR) 的吊灯轴突盒的密度在青春期显着下降。由于 PV 和 GAT1 的减少会增加 GABA 对重复刺激的释放和功效，因此青春期时墨盒中 PV 和 GAT1 的下降可能会大大增强锥体细胞输出的吊灯神经元调节，并有助于工作记忆性能的成熟。因此，所提出的研究旨在确定青春期猴子 DLPFC 吊灯神经元的正常成熟是否增强了它们调节锥体细胞输出和在伽马频率下同步较大锥体细胞群活动的能力。目标 1-3 检验了青春期与墨盒中 PV 和 GAT1 蛋白减少相关的假设，目标 4 检验了以下假设：这些变化与在工作记忆期间存在的重复放电下枝形吊灯神经元输入锥体细胞的功效增加有关任务。目标 5 检查青春期期间枝形吊灯细胞的变化，这些变化可能会增加其产生伽马振荡的能力，目标 6 测试青春期 DLPFC 中的伽马带功率增加的假设。拟议研究的优势包括将解剖学、分子和电生理学技术整合到灵长类动物模型系统中，以探索工作记忆性能正常成熟的细胞和电路基础，并了解精神分裂症工作记忆功能障碍的病理生理学。