Delineating NMDA Receptor Hypofunctions Role in Schizophrenia Pathophysiology

描述(申请人提供)：NMDAR拮抗剂，包括苯环利定、氯胺酮和MK-801，在人类受试者中引起精神反应，类似于导致精神分裂症病理生理学的NMDAR功能低下假说的许多精神分裂症症状。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拮抗剂还可以恢复稳定的精神分裂症患者原有的症状。遗传学研究为这一理论提供了进一步的证据。例如，一只NR1亚基蛋白表达降低到5-10%的NR1亚基蛋白表达低下的小鼠，表现出社交能力的缺陷和声惊厥反射脉冲前抑制的损害。然而，在哪个发育阶段和/或在哪个脑细胞类型/区域中，NMDAR功能低下是诱导精神分裂症样行为所必需的，这一点仍有待确定。我们最近证明，从出生后2周起，大脑皮质边缘间神经元中NMDAR的限制性缺失足以引发小鼠的一些类似人类精神分裂症的行为和病理生理学特征。因此，这为长期以来关于皮层中间神经元NMDAR功能低下是精神分裂症发病的主要部位的假说提供了有力的实验支持。然而，许多编码NMDAR复合体蛋白的基因，如神经调节素，在大脑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功能低下。此外，目前还不清楚哪个发育阶段是NMDAR功能低下的敏感期。最后，关键是要确定在NR1缺失的中间神经元中发生了什么，以及在NMDAR缺失后，哪些下游信号级联/电路被激活或抑制。为了利用转基因小鼠解决这些问题，本项目中需要研究的两个主要重叠领域是：1.确定NMDAR功能低下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功能低下的边界条件是至关重要的，以便描绘NMDAR功能低下的下游途径，并确定哪些途径对疾病的后期发展负责。2.确定敏感期NMDAR功能减退后的细胞事件。为了开发针对NMDAR功能低下的人类精神疾病的新疗法，描述NMDAR功能低下后的后续分子、细胞和网络事件将是至关重要的。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对精神分裂症的治疗提供新的见解。

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.