DISC1 in Neuron-Astrocyte Interactions in Neurodevelopment

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，参与精神分裂症中谷氨酸的异常传递。丝氨酸消旋酶（SR）直接将L-丝氨酸转化为d -丝氨酸，存在于星形胶质细胞和神经元中。我们的前期研究表明，DISC1与SR结合并调节星形胶质细胞产生d-丝氨酸。我们假设异常的DISC1-SR相互作用会影响d -丝氨酸代谢，导致异常的谷氨酸神经传递和由此产生的精神分裂症相关行为。特异性目的1将确定DISC1-SR相互作用的机制。我们将绘制这两种蛋白的结合域，并比较星形胶质细胞和神经元中SR与DISC1的结合。特异性目的2将确定DISC1在d -丝氨酸产生调控中的作用。我们将阐明DISC1的变化如何影响神经元和星形胶质细胞中SR和d -丝氨酸代谢水平。特异性目的3将评估DISC1-SR相互作用在皮层和海马中谷氨酸能突触传递中的作用。我们将确定突变体DISC1在星形胶质细胞和神经元中的表达是否会改变谷氨酸能突触传递的不同参数。特异性目标4将确定SR-DISC1相互作用对精神分裂症样行为的影响。我们将探索转基因小鼠的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 -环丝氨酸来挽救。该资助申请将揭示DISC1与SR相互作用调节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。

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.