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.

抽象的在精神分裂症中经常观察到的伽马范围的神经元同步异常可能与认知缺陷。尽管有证据表明靶向锥体细胞的皮质快速刺激性中间神经元可能参与神经元同步，精神分裂症中神经元同步异常的细胞基础尚待确定。我们最近证明了皮质中NMDA受体的早期删除大多数含有白蛋白的海马中间神经元足以触发几个与人类精神分裂症相似的小鼠的病理生理特征。突变小鼠表现出几个行为认知样缺陷和对惊吓反射的预硫化。他们也显示出衰落的皮质锥体细胞之间的尖峰同步与音调诱发的伽马频率振荡不足通过体内记录测量的听觉皮层中局部场电位的活性。描述 NMDA受体后突触后神经元的同步发射障碍的基本机制在皮质中间神经元中消融。我们最近发现，糖原合酶激酶3（GSK3）是上升的在NMDAR删除的快速刺激性中间神经元中，调节和CAV2.1（P/Q-Type）通道电流减少突变小鼠的此外，抑制GSK3活性增强了CAV2.1通道电流，并且在很大程度上缓解同步GABA释放后的缺陷。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，这会损害同步的GABA释放和同步的皮质中产生认知功能障碍的振荡。这此应用的目的是确定NMDA中GSK3和CAV2.1通道的失调是否失调受体排除的快速刺激神经元对于同步的GABA释放而言至关重要这些分子的功能恢复不仅挽救了体内异常神经元同步，还可以挽救行为认知功能障碍。提出的研究可能会产生对细胞机制的新见解皮质神经元同步，有可能导致开发新的药物，以导致认知功能障碍精神分裂症患者，目前在医学上是棘手的。