de Bartolomeis Andrea, Latte Gianmarco, Tomasetti Carmine, Iasevoli Felice
Laboratory of Molecular and Translational Psychiatry, Unit of Treatment Resistant Psychosis, Department of Neuroscience, Reproductive and Odontostomatologic Sciences, Section of Psychiatry, University School of Medicine "Federico II", Via Pansini 5, 80131, Naples, Italy,
Mol Neurobiol. 2014 Feb;49(1):484-511. doi: 10.1007/s12035-013-8534-3. Epub 2013 Sep 3.
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.
新兴研究表明，突触后致密区（PSD）蛋白，如PSD - 95、Homer、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发挥着重要作用。PSD是一种在电子显微镜下可检测到的厚度结构，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；它被认为是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、5 - 羟色胺能和谷氨酸能系统，这些系统均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。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相关。Shank基因的突变在自闭症谱系障碍患者中已被识别，并且在基因工程小鼠中表达时，据报道与类似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，从而影响与精神病病理生理学相关脑区的PSD蛋白。我们最终提供了一个框架，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及相关疾病新治疗方法的有用候选物，在这些疾病中，需要新的生物治疗方法，尤其是针对一些当前抗精神病药物疗效不佳的症状领域，如阴性症状。
