DISC1 in Neuron-Astrocyte Interactions in Neurodevelopment

神经发育中神经元-星形胶质细胞相互作用中的 DISC1

• 批准号: 9054924
• 负责人: Mikhail V Pletnikov
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9054924
• 关键词: Affect; Animal Model; Applications Grants; Astrocytes; Behavior; Binding; Binding Sites; Candidate Disease Gene; Cells; Cycloserine; DISC1 gene; Dominant-Negative Mutation; Enzymes; Foundations; Functional disorder; Genes; Glutamates; Glycine; Grant; Hippocampus (Brain); Human; In Vitro; Ligands; Link; Maps; Mental disorders; Metabolism; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; Neurobehavioral Manifestations; Neuroglia; Neurons; Neurotransmitters; Personal Communication; Physiology; Pilot Projects; Production; Proteins; Regulation; Reporting; Role; Schizophrenia; Serine; Site; Synapses; Synaptic Transmission; System; Testing; Therapeutic Clinical Trial; Transgenic Mice; Ulysses Contracts; cell type; dopamine system; frontal lobe; glutamatergic signaling; improved; in vivo; inducible gene expression; insight; mouse model; mutant; neurodevelopment; neurotransmission; research study; serine racemase; targeted treatment; transmission process

DESCRIPTION (provided by applicant): D-serine is a selective endogenous activator of the NMDAR D-serine/glycine site that is involved in abnormal glutamate transmission in schizophrenia. The enzyme serine racemase (SR) directly converts L- serine to D-serine and is present in astrocytes and neurons. Our pilot studies indicated that Disrupted-In- Schizophrenia-1 (DISC1) binds to SR and regulate D-serine production by astrocytes. We hypothesize that abnormal DISC1-SR interaction will affect D-serine metabolism, leading to abnormal glutamatergic neurotransmission and resultant schizophrenia-relevant behaviors. Specific Aim 1 will determine the mechanisms of DISC1-SR interaction. We will map binding domains for both proteins and compare binding of SR to DISC1 in astrocytes vs. neurons. Specific Aim 2 will determine the role of DISC1 in the regulation of D-serine production. We will elucidate how changes in DISC1 affect levels of SR and D-serine metabolism in neurons vs. astrocytes. Specific Aim 3 will evaluate the role of DISC1-SR interaction in glutamatergic synaptic transmission in the cortex and hippocampus. We will determine whether expression of mutant DISC1 in astrocytes vs. neurons alters different parameters of glutamatergic synaptic transmission. Specific Aim 4 will identify the effects of SR-DISC1 interaction on schizophrenia-like behaviors. We will probe schizophrenia-related behaviors in transgenic mice and determine whether these phenotypic changes can be rescued with D-serine and/or D-cycloserine. The grant application will uncover the molecular mechanisms whereby DISC1 interacts with SR to regulate D-serine production and influences glutamate neurotransmission and schizophrenia-like behaviors.

描述（由申请人提供）：D-丝氨酸是NMDAR D-丝氨酸/甘氨酸位点的选择性内源性激活剂，其参与精神分裂症中的异常谷氨酸传递。丝氨酸消旋酶（SR）直接将L-丝氨酸转化为D-丝氨酸，并且存在于星形胶质细胞和神经元中。我们的初步研究表明，Disrupted-In- Schizophrenia-1（DISC 1）与SR结合并调节星形胶质细胞的D-丝氨酸产生。我们假设异常DISC 1-SR相互作用将影响D-丝氨酸代谢，导致异常的多巴胺能神经传递和精神分裂症相关行为。 具体目标1将确定DISC 1-SR相互作用的机制。我们将绘制这两种蛋白质的结合结构域，并比较星形胶质细胞与神经元中SR与DISC 1的结合。 具体目标2将确定DISC 1在调节D-丝氨酸产生中的作用。我们将阐明DISC 1的变化如何影响神经元与星形胶质细胞中SR和D-丝氨酸代谢的水平。 具体目标3将评估DISC 1-SR相互作用在皮质和海马中的突触传递中的作用。我们将确定突变DISC 1在星形胶质细胞和神经元中的表达是否改变了神经元能突触传递的不同参数。 具体目标4将确定SR-DISC 1相互作用对精神分裂症样行为的影响。我们将在转基因小鼠中探索精神分裂症相关行为，并确定这些表型变化是否可以用D-丝氨酸和/或D-环丝氨酸挽救。该基金申请将揭示DISC 1与SR相互作用以调节D-丝氨酸产生并影响谷氨酸神经传递和精神分裂症样行为的分子机制。