Delineating NMDA Receptor Hypofunctions Role in Schizophrenia Pathophysiology

描述（由申请人提供）：NMDAR拮抗剂，包括苯环利定、氯胺酮和MK-801，在人类受试者中诱导类似于许多精神分裂症症状的精神病反应，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拮抗剂也会使稳定型精神分裂症患者原有的症状恢复。基因研究为这一理论提供了进一步的证据。例如，NR1亚基蛋白表达减少5- 10%的NR1低变形小鼠表现出社会交往缺陷和声惊反射脉冲前抑制功能受损。然而，在哪个发育阶段和/或哪个脑细胞类型/区域，NMDAR功能低下是诱发精神分裂症样行为所必需的，仍有待确定。我们最近证明，从出生后第2周开始，皮质边缘中间神经元中NMDAR的限制性缺失足以引发与人类精神分裂症相似的小鼠的几种行为和病理生理特征。因此，这为长期以来的假设提供了强有力的实验支持，即皮质中间神经元NMDAR功能障碍是精神分裂症发病的主要部位。然而，许多编码NMDAR复合体蛋白的基因，如神经调节蛋白，在皮层的兴奋性和抑制性神经元中都有表达。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，哪个发育阶段是NMDAR功能减退的敏感期尚不清楚。最后，确定NMDAR缺失后nr1缺失的中间神经元中发生了什么以及哪些下游信号级联/回路被激活或抑制是至关重要的。为了利用转基因小鼠解决这些问题，本项目将研究两个主要重叠的领域：1。明确NMDAR功能减退的细胞类型和敏感期，这对精神分裂症样表型的表现至关重要。缩小NMDAR功能减退的边界条件是至关重要的，以便描绘NMDAR功能减退的下游途径，并确定哪些途径负责疾病的后期发展。2. 确定敏感期NMDAR功能减退后的细胞事件。为了开发针对人类精神疾病NMDAR功能减退的新疗法，描述NMDAR功能减退后的分子、细胞和网络事件将是至关重要的。这些发现将为精神分裂症的皮质gaba能中间神经元相关发病机制及其治疗提供新的见解。

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.