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扰动，其与树突棘密度的减少以及海马和皮质的萎缩有关。这些突触干扰的原因可能涉及大量风险基因和途径，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。虽然有显著的证据表明，NMDAR功能减退有助于精神分裂症的病理生理，有鲜为人知的事件下游的NMDAR负责调节树突可塑性在体内。此外，目前还不清楚是否遗传损伤，干扰amatergic传输不同的分子机制冲击收敛信号级联。因此，本提案的目标是利用两种海马能传递受损的突变小鼠模型，丝氨酸消旋酶缺陷（SR-/-）和dysbindin缺陷（dys-/-）小鼠，以确定由NMDAR活性调节的共同最终途径中的干扰，这些干扰有助于海马神经可塑性受损，并确定这些缺陷是否可以通过药理学干预逆转。我们的实验室已经产生了一种缺乏SR的突变小鼠，SR是一种将L-丝氨酸转化为D-丝氨酸的酶，它会使D-丝氨酸减少90%，并伴有NMDAR功能减退。D-丝氨酸的缺乏导致整体NMDAR介导的神经传递降低，并且对海马中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-/-小鼠中重现，因为SR-/-小鼠减少了：齿状颗粒细胞（DGC）上的树突棘密度，BDNF mRNA和蛋白质，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。该提案的目标1将在最初的2年指导K99阶段完成，将确定SR-/-小鼠中miR-132表达减少的分子机制，测试miR-132失调是否是其树突异常的原因，并确定通过lenti-miR-132过表达逆转SR-/-小鼠中的树突棘异常是否恢复了它们的认知功能。目标2和3将在随后的3年独立R 00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-/-小鼠中的树突状细胞、神经营养细胞和miR-132表达异常。目的3将确定dys-/-小鼠（也具有受损的突触能传递）是否具有与BDNF/Akt信号传导和miR-132减少相关的树突棘缺陷，类似于在SR-/-小鼠中观察到的。总之，这一建议将有助于阐明与NMDAR功能减退相关的机制，这些机制是导致精神分裂症中突触缺陷和神经可塑性受损的原因。然后，这些新的途径可以作为精神分裂症以及其他表现出树突棘病变的大脑和精神疾病的治疗干预的目标。

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.