NMDA receptor hypofunction contributes to the dendritic dysplasia in schizophreni

描述（由申请人提供）：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通性的紊乱，这与树突棘密度的减少和海马和皮质的萎缩有关。这些突触紊乱的原因可能涉及大量的风险基因和途径，其中许多最强的候选基因直接与n -甲基- d -天冬氨酸受体（NMDAR）相互作用。虽然有重要的证据表明NMDAR功能障碍有助于精神分裂症的病理生理，但对于NMDAR下游负责调节体内树突可塑性的事件知之甚少。此外，目前尚不清楚通过不同分子机制干扰谷氨酸能传递的遗传损伤是否会影响趋同信号级联。因此，本研究的目的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-/-）和结合异常缺陷（dys-/-）小鼠，确定NMDAR活性调节的常见最终通路的紊乱，这些紊乱导致海马神经可塑性受损，并确定这些缺陷是否可以通过药物干预来逆转。我们的实验室产生了一种缺乏SR的突变小鼠，SR是一种将l -丝氨酸转化为d -丝氨酸的酶，导致d -丝氨酸减少90%，并伴有NMDAR功能减退。d -丝氨酸的缺乏导致nmda介导的神经传递减少，海马对LTP诱导的敏感性降低。我的初步研究结果表明，在精神分裂症中观察到的海马异常在我们的SR-/-小鼠中得到了再现，SR-/-小鼠减少了：齿状颗粒细胞（DGCs）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的原代、前体和成熟转录本的表达。本提案的目的1将在最初2年的K99指导阶段完成，将确定SR-/-小鼠中miR-132表达降低的分子机制，测试miR-132失调是否导致其树突异常，并确定通过lentii -miR-132过表达逆转SR-/-小鼠的树突脊柱异常是否恢复其认知功能。目标2和目标3将在随后的3年独立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-/-小鼠的树突、神经营养和miR-132表达异常。Aim 3将确定同样具有谷氨酸能传递受损的day -/-小鼠是否具有树突状脊柱缺陷，这种缺陷与BDNF/Akt信号和miR-132的减少有关，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功能障碍相关的机制，NMDAR功能障碍是导致精神分裂症突触缺陷和神经可塑性受损的原因。这些新的通路可以用于精神分裂症的治疗干预，以及其他表现出树突脊柱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.