NMDA receptor hypofunction contributes to the dendritic dysplasia in schizophreni

描述(申请人提供)：精神分裂症是一种复杂的精神障碍，影响全球1%的人口。精神分裂症的主要病理特征之一是突触连接的紊乱，这与树突密度的减少和海马区和皮质的萎缩有关。这些突触障碍的原因可能涉及大量的危险基因和途径，许多最强大的候选基因直接与N-甲基-D-天冬氨酸受体(NMDAR)相互作用。尽管有重要证据表明NMDAR功能低下与精神分裂症的病理生理学有关，但对NMDAR下游在体内调节树突状可塑性的事件知之甚少。此外，尚不清楚通过不同的分子机制扰乱谷氨酸能传递的遗传侮辱是否会影响收敛的信号级联反应。因此，这项建议的目标是利用两种谷氨酸能传递受损的突变小鼠模型，即丝氨酸消旋酶缺陷(SR-/-)和异常结合素缺乏(Dys-/-)小鼠，以确定在共同的最终通路中由NMDAR活性调节的导致海马神经可塑性损害的干扰，并确定这些缺陷是否可以通过药物干预来逆转。我们的实验室已经培育出一只缺乏SR的突变小鼠，SR是一种将L-丝氨酸转化为D-丝氨酸的酶，它导致D-丝氨酸减少90%，同时NMDAR功能减退。这种D-丝氨酸的缺乏导致NMDAR介导的整体神经传递减少，并降低了对海马区LTP诱导的敏感性。我的初步研究结果表明，在我们的SR-/-小鼠中观察到的精神分裂症患者的海马区异常可以概括为SR-/-小鼠：齿状颗粒细胞(DGC)上的树突棘密度、BDNF mRNA和蛋白、磷酸化TrkB(活性形式)、磷酸化Akt(活性形式)以及miR-132的初级、前体和成熟转录本的表达。这项建议的目标1将在最初的两年指导K99阶段完成，将确定SR-/-小鼠miR-132表达减少的分子机制，测试miR-132调节失调是否导致它们的树突异常，并确定通过Lenti-miR-132过表达逆转SR-/-小鼠的树突棘异常是否恢复了它们的认知功能。目标2和目标3将在随后为期3年的独立R00阶段完成。目的2将确定慢性D-丝氨酸或TrkB激动剂治疗是否可以逆转SR-/-小鼠树突状细胞、神经营养和miR-132的表达异常。目的3将确定也有谷氨酸能传递受损的Dys-/-小鼠是否存在树突棘缺陷，这种缺陷与BDNF/Akt信号和miR-132减少有关，类似于在SR-/-小鼠中观察到的情况。总之，这一建议将有助于阐明与NMDAR功能低下有关的机制，这些机制是导致精神分裂症突触缺陷和神经可塑性受损的原因。然后，这些新的通路可以作为治疗干预的靶点，用于精神分裂症以及其他表现出树突棘状病理的大脑和精神疾病。

DESCRIPTION (provided by applicant): Schizophrenia is a complex mental disorder that affects 1% of the population worldwide. One of the cardinal pathological features of schizophrenia is perturbation in synaptic connectivity that is associated with reductions in dendritic spine density and atrophy of the hippocampus and cortex. The cause of these synaptic disturbances likely involves a large number of risk genes and pathways, with many of the strongest candidates interacting directly with the N-methyl-D-aspartate receptor (NMDAR). Although there is significant evidence suggesting that NMDAR hypofunction contributes to the pathophysiology of schizophrenia, there is little known about the events downstream of the NMDAR that are responsible for regulating dendritic plasticity in vivo. Moreover, it is unclear whether genetic insults that perturb glutamatergic transmission by distinct molecular mechanisms impinge on convergent signaling cascades. Thus, the goals of this proposal are to utilize two mutant mouse models with impaired glutamatergic transmission, serine racemase deficient (SR-/-) and dysbindin deficient (dys-/-) mice, to identify disturbances in common final pathways regulated by NMDAR activity that contribute to impairments in hippocampal neuroplasticity, and determine whether these deficiencies can be reversed by pharmacological intervention. Our laboratory has generated a mutant mouse that lacks SR, the enzyme that converts L-serine to D-serine, which produces a 90% reduction in D-serine coupled with NMDAR hypofunction. This lack of D-serine results in decreased global NMDAR-mediated neurotransmission and reduced sensitivity to the induction of LTP in the hippocampus. My preliminary findings have shown that the hippocampal abnormalities observed in schizophrenia are recapitulated in our SR-/- mice, in that SR-/- mice have reduced: dendritic spine density on dentate granule cells (DGCs), BDNF mRNA and protein, phospho-TrkB (active form), phospho-Akt (active form), and expression of the primary, precursor, and mature transcripts of miR-132. Aim 1 of this proposal, which will be completed during the initial 2 year mentored K99 phase, will determine the molecular mechanisms responsible for the reduced miR-132 expression in SR-/- mice, test whether miR-132 dysregulation is responsible for their dendritic abnormalities, and determine whether reversing the dendritic spine abnormalities in SR-/- mice via lenti-miR-132 overexpression restores their cognitive function. Aims 2 and 3 will be completed during the subsequent 3-year independent R00 phase. Aim 2 will determine whether chronic D-serine or TrkB agonist treatment can reverse the dendritic, neurotrophic, and miR-132 expression abnormalities in SR-/- mice. Aim 3 will determine if dys-/- mice, which also have impaired glutamatergic transmission, have dendritic spine deficits that are associated with reductions in BDNF/Akt signaling and miR-132, similar to what is observed in SR-/- mice. In sum, this proposal will help to elucidate the mechanisms associated with NMDAR hypofunction that are responsible for causing the synaptic deficits and impaired neuroplasticity in schizophrenia. These novel pathways can then be targeted for therapeutic intervention in schizophrenia, as well as other brain and psychiatric disorders that exhibit dendritic spine pathologies.