GRIN2A and Schizophrenia: Scientific Evidence and Biological Mechanisms.

IF 4.8 2区 医学 Q1 NEUROSCIENCES
Xiao-Ming Sheng, Wei Guan
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Abstract

Schizophrenia is a severe psychiatric disorder and a complex polygenic inherited disease that affects nearly 1% of the global population. Although considerable progress has been made over the past 10 years in the treatment of schizophrenia, antipsychotics are not universally effective and may have serious side effects. The hypofunction of glutamate NMDA receptors (NMDARs) in GABAergic interneurons has long been postulated to be the principal pathophysiology of schizophrenia. A recent study has shown that GRIN2A pathogenic variants are closely related to the aetiology of the disorder. GRIN2A encodes the GluN2A protein, which is a subunit of NMDAR. Most GRIN2A variants have been predicted to cause protein truncation, which results in reduced gene expression. Preclinical studies have indicated that GRIN2A mutations lead to NMDAR loss of function and substantially increase the risk of schizophrenia; however, their role in schizophrenia is not well understood. We hypothesise that the heterozygous loss of GRIN2A induces NMDAR hypofunction sufficient to confer a substantial risk of schizophrenia. Therefore, this review focuses on GRIN2A as a target for novel antipsychotics and discusses the mechanisms by which GRIN2A modulates antischizophrenic activities. Moreover, our review contributes to the understanding of the pathophysiology of schizophrenia to facilitate finding treatments for the cognitive and negative symptoms of schizophrenia.

GRIN2A 与精神分裂症:科学证据和生物机制。
精神分裂症是一种严重的精神疾病,也是一种复杂的多基因遗传病,全球近 1%的人口患有此病。尽管过去 10 年来精神分裂症的治疗取得了长足的进步,但抗精神病药物并非普遍有效,而且可能会产生严重的副作用。长期以来,人们一直认为 GABA 能中间神经元中的谷氨酸 NMDA 受体(NMDARs)功能低下是精神分裂症的主要病理生理学原因。最近的一项研究表明,GRIN2A致病变体与精神分裂症的病因密切相关。GRIN2A 编码 GluN2A 蛋白,它是 NMDAR 的一个亚基。据预测,大多数 GRIN2A 变体都会导致蛋白质截断,从而导致基因表达减少。临床前研究表明,GRIN2A 基因突变会导致 NMDAR 功能丧失,并大大增加精神分裂症的患病风险;然而,它们在精神分裂症中的作用还不十分清楚。我们假设,GRIN2A 的杂合性缺失会诱导 NMDAR 功能缺失,足以导致精神分裂症的重大风险。因此,本综述侧重于将 GRIN2A 作为新型抗精神病药物的靶点,并讨论 GRIN2A 调节抗精神分裂症活性的机制。此外,我们的综述还有助于人们了解精神分裂症的病理生理学,从而找到治疗精神分裂症认知症状和阴性症状的方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Current Neuropharmacology
Current Neuropharmacology 医学-神经科学
CiteScore
8.70
自引率
1.90%
发文量
369
审稿时长
>12 weeks
期刊介绍: Current Neuropharmacology aims to provide current, comprehensive/mini reviews and guest edited issues of all areas of neuropharmacology and related matters of neuroscience. The reviews cover the fields of molecular, cellular, and systems/behavioural aspects of neuropharmacology and neuroscience. The journal serves as a comprehensive, multidisciplinary expert forum for neuropharmacologists and neuroscientists.
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