PDF(Pubmed)
Abstract：
Bridging the gap between preclinical models of neurological and psychiatric disorders with their human manifestations is necessary to understand their underlying mechanisms, identify biomarkers, and develop novel therapeutics. Cognitive and social impairments underlie multiple neuropsychiatric and neurological disorders and are often comorbid with sleep disturbances, which can exacerbate poor outcomes. Importantly, many symptoms are conserved between vertebrates and invertebrates, although they may have subtle differences. Therefore, it is essential to determine the molecular mechanisms underlying these behaviors across different species and their translatability to humans. Genome-wide association studies have indicated an association between glutamatergic gene variants and both the risk and frequency of psychiatric disorders such as schizophrenia, bipolar disorder, and autism spectrum disorder. For example, changes in glutamatergic neurotransmission, such as glutamate receptor subtype N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been shown to contribute to the pathophysiology of schizophrenia. Furthermore, in neurological disorders, such as traumatic brain injury and Alzheimer\'s disease, hyperactivation of NMDARs leads to synaptic damage. In addition to glutamate binding, NMDARs require the binding of a co-agonist D-serine or glycine to the GluN1 subunit to open. D-serine, which is racemized from L-serine by the neuronal enzyme serine racemase (SRR), and both SRR and D-serine are enriched in cortico-limbic brain regions. D-serine is critical for complex behaviors, such as cognition and social behavior, where dysregulation of its synthesis and release has been implicated in many pathological conditions. In this review, we explore the role of D-serine in behaviors that are translationally relevant to multiple psychiatric and neurological disorders in different models across species.
摘要：
弥合神经和精神疾病的临床前模型与人类表现之间的差距是必要的，以了解其潜在的机制，识别生物标志物，并开发新的疗法。认知和社交障碍是多种神经精神和神经系统疾病的基础，通常与睡眠障碍并存。这会加剧糟糕的结果。重要的是,许多症状在脊椎动物和无脊椎动物之间是保守的，尽管它们可能有细微的差异。因此,确定这些行为在不同物种之间的潜在分子机制及其对人类的可翻译性至关重要。全基因组关联研究表明，谷氨酸能基因变异与精神分裂症等精神疾病的风险和频率之间存在关联。双相情感障碍,和自闭症谱系障碍。例如,谷氨酸能神经传递的变化，如谷氨酸受体亚型N-甲基-D-天冬氨酸受体（NMDAR）功能减退，已被证明有助于精神分裂症的病理生理学。此外，在神经系统疾病中，比如创伤性脑损伤和阿尔茨海默病，NMDAR的过度激活导致突触损伤。除了谷氨酸结合，NMDAR需要共同激动剂D-丝氨酸或甘氨酸与GluN1亚基结合才能打开。D-丝氨酸,通过神经元酶丝氨酸消旋酶（SRR）从L-丝氨酸消旋化，SRR和D-丝氨酸都富集在皮质边缘脑区。D-丝氨酸是复杂行为的关键,比如认知和社会行为，在许多病理条件下，其合成和释放的失调都与之有关。在这次审查中,我们探讨了D-丝氨酸在跨物种的不同模型中与多种精神和神经系统疾病翻译相关的行为中的作用。
