The Role of Serine Racemase in the Pathophysiology of Brain Disorders
The Role of Serine Racemase in the Pathophysiology of Brain Disorders
复制标题
DOI：
10.1016/bs.apha.2017.10.002
复制
发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Balu, Darrick T.
中科院分区：
文献类型：
--
作者：
Coyle, Joseph T.;Balu, Darrick T.
N-甲基-D-天冬氨酸受体（NMDAR）的独特之处在于需要两种激动剂同时结合以打开其阳离子通道：神经递质谷氨酸和凝血剂甘氨酸或D-丝氨酸。斯奈德实验室是第一个克隆丝氨酸消旋酶（SR），合成D-丝氨酸的酶，并定位它的免疫细胞化学。我们的实验室专注于D-丝氨酸在大脑疾病中的作用。在小鼠（SR-/-）中沉默SR（精神分裂症（SCZ）的风险基因）的表达，导致与SCZ非常相似的表型，包括：皮质萎缩、树突棘密度和复杂性降低、小清蛋白阳性皮质GABA能神经元下调和认知障碍。这种病理学可以通过在成年期用D-丝氨酸治疗SR-/-小鼠来逆转。SR-/-小鼠也表现出对可滥用物质（如兴奋剂）的异常反应。他们表现出对D-苯丙胺的行为敏感性降低，但未能消除它。可卡因的位置偏好被改变，并且通过颅内自我刺激评估，对可卡因的享乐反应严重受损。D-环丝氨酸是NMDAR甘氨酸调节位点的部分激动剂，与行为疗法组合显示出治疗病理性焦虑的治疗益处。体外皮质培养和体内大脑中动脉闭塞的研究表明，沉默SR提供了实质性的保护，防止缺血性神经元死亡。最后，SR表达的开关从神经元到反应性星形胶质细胞闭合性头部创伤后占在体内神经可塑性降低，脑电图异常，认知障碍。
The N-methyl-D-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or D-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes D-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of D-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR-/-), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine density and complexity, downregulation of parvalbumin-positive cortical GABAergic neurons, and cognitive impairments. This pathology can be reversed by treatment of SR-/- mice with D-serine in adulthood. SR-/- mice also exhibit abnormal response toward abusable substances, such as stimulants. They show reduced behavioral sensitization to D-amphetamine, but fail to extinguish it. Place preference to cocaine is altered, and the hedonic response to it is profoundly impaired as assessed by intracranial self-stimulation. D-cycloserine, a partial agonist at the NMDAR glycine modulatory site, shows therapeutic benefit for treating pathologic anxiety in combination with behavioral therapies. Studies in vitro with cortical culture and in vivo with middle cerebral artery occlusion show that silencing SR provides substantial protection against ischemic neuronal death. Finally, the switch of SR expression from neurons to reactive astrocytes after closed head trauma accounts for the reduced in vivo neuroplasticity, electroencephalogram abnormalities, and cognitive impairments.