Cellular Mechanism of Synchrony Impairments in Schizophrenia

精神分裂症同步性损伤的细胞机制

基本信息

批准号：
9155331
负责人：
Kazutoshi Nakazawa
金额：
$ 58.17万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9155331
关键词：
Ablation Action Potentials Address Adult Agonist Animals Auditory area Behavior Behavioral Characteristics Cognitive Cognitive deficits Data Development Disease Down-Regulation Electrophysiology (science)Engineering Enzymes Exhibits Frequencies Functional disorder Genes Glycogen Synthase Kinase 3 Goals Hippocampus (Brain)Human Impaired cognition Impairment In Vitro Interneurons Ketamine Lead Measures Mediating Mediator of activation protein Membrane Potentials Methods Mission Modeling Mus Mutant Strains Mice N-Methyl-D-Aspartate Receptors NMDA receptor A1 NMDA receptor antagonist Neurons P-Q type voltage-dependent calcium channel Parvalbumins Pathogenesis Phencyclidine Phenotype Physiological Play Preparation Process Protein Isoforms Pyramidal Cells Reflex action Research Role Schizophrenia Short-Term Memory Slice Study models Symptoms System Techniques Testing Transgenic Mice Transgenic Organisms Up-Regulation abstracting base cognitive function functional restoration gamma-Aminobutyric Acid in vivo inhibitor/antagonist insight loss of function mutation mouse model mutant new therapeutic target novel novel therapeutics postnatal postsynaptic neurons prepulse inhibition public health relevance relating to nervous system restoration

项目摘要

Abstract Abnormal neuronal synchrony at gamma range, often observed in schizophrenia, may be associated with cognitive deficits. Although evidence suggests that cortical fast-spiking interneurons targeting pyramidal cells may be involved in neuronal synchrony, cellular basis of abnormal neuronal synchrony in schizophrenia remains to be identified. We recently demonstrated that early postnatal deletion of NMDA receptors in cortical and hippocampal interneurons, majority of which are parvalbumin containing, was sufficient to trigger several pathophysiological features in mice that resemble human schizophrenia. The mutant mice exhibit several behavioral cognitive-like deficits and prepulse inhibition of the startle reflex. They also display a diminished spike synchrony between cortical pyramidal cells and a deficit in tone-evoked gamma frequency oscillatory activity of local field potentials in auditory cortex, measured by in vivo recordings. It is crucial to delineate the underlying mechanisms of the synchronous firing impairment of postsynaptic neurons following NMDA receptor ablation in cortical interneurons. We recently discovered that glycogen synthase kinase 3 (GSK3) is up- regulated and Cav2.1 (P/Q-type) channel currents are diminished in NMDAR-deleted fast-spiking interneurons of the mutant mice. Furthermore, inhibition of GSK3 activity augmented Cav2.1 channel currents and largely ameliorates the deficit in synchronized GABA release ex vivo. We hypothesize that that GSK3 up-regulation in the NMDA receptor-deficient fast-spiking interneurons down-regulates Cav2.1 channel function, which impairs synchronized GABA release and synchronized oscillations in the cortex producing cognitive dysfunction. The objective of this application is to determine whether dysregulation of GSK3 and Cav2.1 channels in the NMDA receptor-deleted fast-spiking neurons is crucial for an impaired synchronized GABA release and whether functional restoration of these molecules rescues not only in vivo abnormal neuronal synchrony but also behavioral cognitive dysfunction. The proposed studies may yield new insights into cellular mechanisms of cortical neuronal synchrony, potentially leading to development of novel drugs for cognitive dysfunction of schizophrenics, which is currently medically intractable.

抽象的经常在精神分裂症中观察到的伽玛范围神经元同步异常可能与认知缺陷。尽管有证据表明皮质快速放电中间神经元靶向锥体细胞可能参与神经元同步，精神分裂症异常神经元同步的细胞基础仍有待确定。我们最近证明，出生后早期皮质中 NMDA 受体的缺失海马中间神经元，其中大部分含有小白蛋白，足以触发一些小鼠的病理生理学特征类似于人类精神分裂症。突变小鼠表现出多种行为认知样缺陷和惊吓反射的前脉冲抑制。它们也表现出减弱的皮质锥体细胞之间的尖峰同步性和音调诱发的伽马频率振荡的缺陷通过体内记录测量听觉皮层局部场电位的活动。划定界限至关重要 NMDA受体后突触后神经元同步放电损伤的潜在机制皮质中间神经元的消融。我们最近发现糖原合成酶激酶 3 (GSK3) 正在上升- NMDAR 删除的快速尖峰中间神经元中的调节通道电流和 Cav2.1（P/Q 型）通道电流减少突变小鼠。此外，抑制 GSK3 活性会增加 Cav2.1 通道电流，并在很大程度上改善离体同步 GABA 释放的缺陷。我们假设 GSK3 上调 NMDA 受体缺陷的快速尖峰中间神经元下调 Cav2.1 通道功能，从而损害同步 GABA 释放和皮质同步振荡产生认知功能障碍。这本申请的目的是确定 NMDA 中的 GSK3 和 Cav2.1 通道是否失调受体缺失的快速尖峰神经元对于 GABA 同步释放受损以及是否这些分子的功能恢复不仅可以挽救体内异常的神经元同步，还可以行为认知功能障碍。拟议的研究可能会对细胞机制产生新的见解皮质神经元同步，可能导致开发治疗认知功能障碍的新药物精神分裂症，目前在医学上是难以治愈的。