Delineating NMDA Receptor Hypofunctions Role in Schizophrenia Pathophysiology

描述 NMDA 受体功能减退在精神分裂症病理生理学中的作用

基本信息

批准号：
8899635
负责人：
Kazutoshi Nakazawa
金额：
$ 29.79万
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：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899635
关键词：
Acoustics Address Adolescence Adult Adverse effects Affect American Amphetamines Animal Model Area Behavior Behavioral Cells Chronic Cognitive Cognitive deficits Delusions Development Disease Dopamine Emotions Event Functional disorder Genes Genetic study Glutamates Goals Hallucinations Health Hippocampus (Brain)Human Impairment Interneurons Intervention Ketamine Knock-out Knowledge Lead Measures Mental disorders Molecular Mus Mutant Strains Mice Mutation N-Methyl-D-Aspartate Receptors NMDA receptor antagonist NR1 gene National Institute of Mental Health Neuregulins Neurobehavioral Manifestations Neurons Parvalbumins Pathogenesis Pathway interactions Patients Persons Pharmaceutical Preparations Phencyclidine Phenotype Play Presynaptic Terminals Process Property Protein Subunits Reaction Reflex action Reporting Research Role Schizophrenia Short-Term Memory Signal Transduction Site Social Interaction Staging Symptoms System Teenagers Testing Thinking Time To specify Transgenic Animals Transgenic Mice Ventral Striatum Withdrawal Work base brain cell cell type excitatory neuron expectation gamma-Aminobutyric Acid hippocampal pyramidal neuron human subject inhibitory neuron innovation insight mutant new therapeutic target postnatal postsynaptic prepulse inhibition presynaptic protein complex social theories

项目摘要

DESCRIPTION (provided by applicant): NMDAR antagonists, including phencyclidine, ketamine and MK-801, induce a psychotic reaction in human subjects that resembles many of schizophrenia symptoms leading the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia pathophysiology. These symptoms include the positive, negative, as well as many of the cognitive deficits, including working memory. Furthermore, NMDAR antagonists also reinstate pre- existing symptoms in stabilized schizophrenia patients. Genetic studies have offered further credence to this theory. For instance, a NR1 hypomorph mouse, in which expression of NR1 subunit protein is reduced to 5- 10%, displays deficits in social interaction and impairment in prepulse inhibition of acoustic startle reflex. Yet, it remains to be determined in which developmental stage and/or in which brain cell-types/areas is NMDAR hypofunction necessary to induce schizophrenia-like behaviors. We recently demonstrated that a restricted deletion of NMDAR in corticolimbic interneurons from postnatal 2nd week was sufficient to trigger several behavioral and pathophysiological features in mice that resemble human schizophrenia. Therefore, it provided strong experimental support for the long-standing hypothesis that NMDAR hypofunction in cortical interneurons is a primary site of schizophrenia pathogenesis. However, many genes encoding the NMDAR complex proteins, such as neuregulins, are expressed in both excitatory and inhibitory neurons in the cortex. If the mutation was introduced in these genes, NMDAR hypofunction could occur in every cell including excitatory neurons. Furthermore, it is still unclear which developmental stage is the sensitive period to NMDAR hypofunction. Finally, it is crucial to identify what occurs in the NR1-deleted interneurons and which downstream signaling cascades/circuitries are activated or suppressed following NMDAR deletion. To address these questions using transgenic mice, two major overlapping areas to be investigated in this project are: 1. Define the cell-types and sensitive period for NMDAR hypofunction critical for the manifestation of schizophrenia-like phenotypes. It is critical to narrow down the boundary conditions of NMDAR hypofunction, in order to delineate the downstream pathways of NMDAR hypofunction and to determine which pathways are responsible for later development of the disease. 2. Determine the cellular events that follow NMDAR hypofunction during the sensitive period. It will be crucial to delineate subsequent molecular, cellular and network events following NMDAR hypofunction, in order to develop the new treatments targeted to NMDAR hypofunction for human psychiatric illnesses. These findings derived from this work will yield new insights into the cortical GABAergic interneuron-related pathogenesis and its treatment of schizophrenia.

描述（由申请人提供）：NMDAR 拮抗剂，包括苯环己哌啶、氯胺酮和 MK-801，会在人类受试者中诱发精神病反应，该反应类似于许多精神分裂症症状，导致精神分裂症病理生理学的 NMDA 受体 (NMDAR) 功能减退假说。这些症状包括积极的、消极的以及许多认知缺陷，包括工作记忆。此外，NMDAR 拮抗剂还可恢复稳定的精神分裂症患者先前存在的症状。遗传学研究进一步证实了这一理论。例如，NR1亚基蛋白表达降低至5-10%的NR1亚型小鼠表现出社交互动缺陷和声惊跳反射前脉冲抑制受损。然而，尚待确定在哪个发育阶段和/或哪个脑细胞类型/区域中 NMDAR 功能减退是诱发精神分裂症样行为所必需的。我们最近证明，从出生后第 2 周起，皮质边缘中间神经元中 NMDAR 的限制性缺失足以引发小鼠的一些类似于人类精神分裂症的行为和病理生理特征。因此，它为长期存在的假设提供了强有力的实验支持，即皮质中间神经元中的 NMDAR 功能低下是精神分裂症发病机制的主要部位。然而，许多编码 NMDAR 复合蛋白的基因（例如神经调节蛋白）在皮层的兴奋性和抑制性神经元中表达。如果在这些基因中引入突变，包括兴奋性神经元在内的每个细胞都可能发生 NMDAR 功能减退。此外，目前尚不清楚哪个发育阶段是NMDAR功能低下的敏感期。最后，确定 NR1 删除的中间神经元中发生的情况以及 NMDAR 删除后哪些下游信号级联/电路被激活或抑制至关重要。为了使用转基因小鼠解决这些问题，本项目要研究的两个主要重叠领域是： 1. 定义对于精神分裂症样表型的表现至关重要的 NMDAR 功能减退的细胞类型和敏感期。缩小 NMDAR 功能低下的边界条件至关重要，以便描绘 NMDAR 功能低下的下游途径并确定哪些途径导致疾病的后期发展。 2. 确定敏感期 NMDAR 功能低下后发生的细胞事件。描述 NMDAR 功能减退后的后续分子、细胞和网络事件至关重要，以便开发针对人类精神疾病的 NMDAR 功能减退的新疗法。这项工作的这些发现将为皮质 GABA 能中间神经元相关的发病机制及其治疗精神分裂症提供新的见解。