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：
8425316
负责人：
Kazutoshi Nakazawa
金额：
$ 29.59万
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 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8425316
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 Glutamates Goals Hallucinations 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 public health relevance 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，包括苯基二肽，氯胺酮和MK-801，在人类受试者中诱导了精神病反应，类似于许多精神分裂症症状，导致NMDA受体（NMDAR）降低了精神分裂症病理生理学的假设。这些症状包括正面，阴性以及许多认知缺陷，包括工作记忆。此外，NMDAR拮抗剂还恢复了稳定的精神分裂症患者的现有症状。遗传研究为该理论提供了进一步的信任。例如，NR1低对形小鼠，其中NR1亚基蛋白的表达降低至5-10％，显示出社交相互作用的缺陷和对声学惊吓反射的预硫化抑制作用。然而，尚待确定在哪个发育阶段和/或脑细胞类型/区域是诱导精神分裂症样行为所需的NMDAR功能低下的。我们最近证明，在产后第二周的Corticolimbic中间神经元中NMDAR的限制缺失足以触发类似于人类精神分裂症的小鼠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功能功能是精神分裂症发病机理的主要部位。但是，许多编码NMDAR复合蛋白（例如神经结合蛋白）的基因在皮质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，则包括兴奋性神经元在内的每个细胞中可能发生NMDAR功能低下。此外，目前尚不清楚哪个发育阶段是NMDAR功能障碍的敏感时期。最后，至关重要的是要确定NR1删除的中间神经元中发生的情况以及在NMDAR删除后激活或抑制哪些下游信号级联/电路。为了使用转基因小鼠解决这些问题，在该项目中要研究的两个主要重叠区域是：1。定义NMDAR功能障碍的细胞类型和敏感时期，对于表现为精神分裂症样表型至关重要。为了描绘NMDAR功能障碍的下游途径，并确定哪些途径是哪些途径造成疾病后期发展，这至关重要。 2。确定在敏感时期遵循NMDAR功能障碍的细胞事件。 NMDAR功能障碍后，至关重要的是描述随后的分子，细胞和网络事件，以开发针对人类精神病的NMDAR功能低下的新疗法。从这项工作中得出的这些发现将为皮质GABA能中与神经元间的发病机理及其对精神分裂症的治疗产生新的见解。