Glutamatergic Postsynaptic Density Protein Dysfunctions in Synaptic Plasticity and Dendritic Spines Morphology: Relevance to Schizophrenia and Other Behavioral Disorders Pathophysiology, and Implications for Novel Therapeutic Approaches
Glutamatergic Postsynaptic Density Protein Dysfunctions in Synaptic Plasticity and Dendritic Spines Morphology: Relevance to Schizophrenia and Other Behavioral Disorders Pathophysiology, and Implications for Novel Therapeutic Approaches
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DOI：
10.1007/s12035-013-8534-3
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发表时间：
2014-02-01
影响因子：
5.1
通讯作者：
Iasevoli, Felice
中科院分区：
文献类型：
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作者：
de Bartolomeis, Andrea;Latte, Gianmarco;Iasevoli, Felice
新兴研究指出突触后致密物（PSD）蛋白，如PSD - 95、荷马蛋白（Homer）、沙克蛋白（Shank）和DISC - 1，在精神分裂症和自闭症谱系障碍的病理生理学中具有相关作用。PSD是一种在电子显微镜下可检测到的厚度，位于谷氨酸能突触的突触后膜，由支架蛋白、受体和效应蛋白组成；它被视为一个结构和功能的交汇点，多个神经递质系统在此汇聚，包括多巴胺能、血清素能和谷氨酸能系统，这些系统都与精神病的病理生理学有关。据报道，精神分裂症患者的尸检大脑中PSD - 95蛋白水平降低。荷马蛋白1（Homer1）是谷氨酸信号传导的关键PSD蛋白，其变体与精神分裂症症状的严重程度和治疗反应有关。沙克基因（Shank gene）的突变已在自闭症谱系障碍患者中被发现，并且据报道当在基因工程小鼠中表达时，与让人联想到精神分裂症症状的行为有关。在此，我们对PSD蛋白在精神分裂症和自闭症谱系障碍病理生理学中的作用进行了批判性评估。然后，我们讨论了抗精神病药物如何可能影响与精神病病理生理学相关的大脑区域中的PSD蛋白，可能是通过调节谷氨酸相关靶点来控制突触可塑性和树突棘重排。我们最后提供了一个框架，该框架可以解释PSD蛋白如何可能成为开发针对精神分裂症和相关疾病的新治疗方法的有用候选者，在这些疾病中需要新的生物治疗方法，特别是针对一些当前抗精神病药物效果不佳的症状领域，如阴性症状。
Emerging researches point to a relevant role of postsynaptic density (PSD) proteins, such as PSD-95, Homer, Shank, and DISC-1, in the pathophysiology of schizophrenia and autism spectrum disorders. The PSD is a thickness, detectable at electronic microscopy, localized at the postsynaptic membrane of glutamatergic synapses, and made by scaffolding proteins, receptors, and effector proteins; it is considered a structural and functional crossroad where multiple neurotransmitter systems converge, including the dopaminergic, serotonergic, and glutamatergic ones, which are all implicated in the pathophysiology of psychosis. Decreased PSD-95 protein levels have been reported in postmortem brains of schizophrenia patients. Variants of Homer1, a key PSD protein for glutamate signaling, have been associated with schizophrenia symptoms severity and therapeutic response. Mutations in Shank gene have been recognized in autism spectrum disorder patients, as well as reported to be associated to behaviors reminiscent of schizophrenia symptoms when expressed in genetically engineered mice. Here, we provide a critical appraisal of PSD proteins role in the pathophysiology of schizophrenia and autism spectrum disorders. Then, we discuss how antipsychotics may affect PSD proteins in brain regions relevant to psychosis pathophysiology, possibly by controlling synaptic plasticity and dendritic spine rearrangements through the modulation of glutamate-related targets. We finally provide a framework that may explain how PSD proteins might be useful candidates to develop new therapeutic approaches for schizophrenia and related disorders in which there is a need for new biological treatments, especially against some symptom domains, such as negative symptoms, that are poorly affected by current antipsychotics.