Molecular Mechanisms of Dendritic Abnormalities Related to D-Serine Deficiency

D-丝氨酸缺乏相关树突异常的分子机制

• 批准号: 7913624
• 负责人: DARRICK T BALU
• 金额: $ 4.76万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913624
• 关键词: Affect; Animal Model; Antipsychotic Agents; Binding Proteins; Brain region; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium/calmodulin-dependent protein kinase; Clinical; Cognitive; Cognitive deficits; Coupled; Cyclic AMP; Disease; Exhibits; Functional disorder; Genetic Transcription; Glycine; Impaired cognition; Mediating; Messenger RNA; Methyl-CpG-Binding Protein 2; MicroRNAs; Mitogen-Activated Protein Kinases; Molecular; Morphogenesis; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Neurites; Neuronal Plasticity; Neurons; Pathway interactions; Pattern; Pharmaceutical Preparations; Prefrontal Cortex; Proteins; Receptor Signaling; Regulation; Research; Response Elements; Sarcosine; Schizophrenia; Serine; Signal Transduction; Site; Testing; Therapeutic; Transcription Repressor/Corepressor; Translations; atypical antipsychotic; mutant; novel; public health relevance; research study; serine racemase

DESCRIPTION (provided by applicant): There is significant evidence that N-methyl-D-aspartate receptor (NMDAR) hypofunction is a core etiological component of schizophrenia. Serine racemase null mutant (SRKO) mice have hypofunctional NMDAR signaling and exhibit reductions in cortical dendritic morphology, similar to what is observed in schizophrenia. The proposed experiments will examine NMDAR-dependent molecular mechanisms responsible for producing the dendritic alterations in SRKO mice. Calcium (Ca2+) influx through NMDARs activates Ca2+/calmodulin (CaM) kinase (CaMK) and mitogen-activated protein kinase (MAPK) signaling. These pathways modulate cAMP/Ca2+ response element binding protein (CREB)-dependent transcription and are involved in NMDAR activity-dependent changes in dendritic plasticity. Aim 1 will determine whether NMDAR hypofunction negatively impacts the activity of CaMK and MAPK signaling in the prefrontal cortex (PFC). microRNAs (miRs) have been implicated in the pathophysiology of schizophrenia. They regulate neural plasticity by controlling the translation of target mRNAs. miR-132 is enriched in neurons, regulates basal and activity-induced neurite outgrowth, and its expression is regulated by CREB. The transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) is a target of miR-132 regulation and modulates activity-dependent dendritic patterning. Aim 2 will determine if NMDAR hypofunction reduces the CREB-mediated transcription of miR-132 in the PFC, and the mRNA and protein levels of MeCP2. Primary cortical cultures will be used to directly test whether miR-132 over-expression enhances dendritic morphology and reduces MeCP2 levels. Cognitive disturbances are a well-defined component of schizophrenia and are coupled with altered functioning of the PFC, the brain region most associated with dendritic abnormalities. Clinical evidence suggests that typical antipsychotics are not effective, while atypical antipsychotics are associated with some cognitive benefit. D-serine and N[3-(4'-fluorophenyl)-3-(4' phenylphenoxy) propyl] sarcosine (NFPS), drugs that enhance NMDAR signaling via the glycine modulatory site (GMS), have pro-cognitive effects in pharmacological animal models of schizophrenia. However, little is known about how antipsychotics and GMS modulators regulate dendritic morphogenesis. Therefore, Aim 3 will use cultured cortical neurons from WT and SRKO mice to compare the ability of typical and atypical antipsychotics, as well as D-serine and NFPS, to affect dendritic plasticity. PUBLIC HEALTH RELEVANCE: Clinically available drugs for schizophrenia are not effective at treating the cognitive deficits. The current research aims to discover new underlying causes of the disease in the hopes of developing novel acting therapeutics that will more completely treat the illness.

描述（由申请人提供）： 有重要证据表明，N-甲基-D-天冬氨酸受体（NMDAR）功能低下是精神分裂症的核心病因组成部分。丝氨酸消旋酶无效突变（SRKO）小鼠具有功能减退的NMDAR信号传导，并且表现出皮质树突形态的减少，类似于在精神分裂症中观察到的。拟议的实验将检查负责产生SRKO小鼠树突状细胞改变的NMDAR依赖性分子机制。通过NMDAR的钙（Ca 2+）内流激活Ca 2 +/钙调蛋白（CaM）激酶（CaMK）和丝裂原活化蛋白激酶（MAPK）信号传导。这些途径调节cAMP/Ca 2+反应元件结合蛋白（CREB）依赖性转录，并参与NMDAR活性依赖性树突可塑性的变化。目的1将确定NMDAR功能减退是否会对前额叶皮层（PFC）中的CaMK和MAPK信号转导活性产生负面影响。 microRNA（miRs）与精神分裂症的病理生理学有关。它们通过控制靶mRNA的翻译来调节神经可塑性。miR-132在神经元中富集，调节基础和活动诱导的神经突生长，其表达受CREB调节。转录抑制因子甲基-CpG结合蛋白2（MeCP 2）是miR-132调控的靶点，并调节活性依赖性树突状模式。目的2将确定NMDAR功能减退是否降低PFC中CREB介导的miR-132转录以及MeCP 2的mRNA和蛋白水平。原代皮质培养物将用于直接测试miR-132过表达是否增强树突状形态并降低MeCP 2水平。 认知障碍是精神分裂症的一个明确的组成部分，并与PFC功能的改变相结合，PFC是与树突异常最相关的大脑区域。临床证据表明，典型的抗精神病药物是无效的，而非典型的抗精神病药物与一些认知的好处。D-丝氨酸和N[3-（4 '-氟苯基）-3-（4'苯基苯氧基）丙基]肌氨酸（NFPS）是通过甘氨酸调节位点（GMS）增强NMDAR信号传导的药物，在精神分裂症的药理学动物模型中具有促认知作用。然而，很少有人知道抗精神病药物和GMS调节剂如何调节树突状形态发生。因此，目标3将使用来自WT和SRKO小鼠的培养的皮层神经元来比较典型和非典型抗精神病药物以及D-丝氨酸和NFPS影响树突可塑性的能力。 公共卫生相关性： 临床上可用的精神分裂症药物对治疗认知缺陷无效。目前的研究旨在发现这种疾病的新的潜在原因，希望开发出更全面治疗这种疾病的新型治疗方法。