gaba能皮质缺陷主导着精神分裂症的病理生理。

E Costa, J M Davis, E Dong, D R Grayson, A Guidotti, L Tremolizzo, M Veldic
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引用次数: 125

摘要

一些证据支持表观遗传诱导的gaba能皮质功能障碍在精神分裂症精神病理中的作用,这可能依赖于gaba能神经元中选择性发生的dna甲基转移酶-1表达的增加。调节GABA合成的关键酶谷氨酸脱羧酶67 (GAD67)和重要的神经发育蛋白reelin在GABA能神经元中共表达。释放后,GABA和reelin与位于锥体神经元树突、体细胞或轴突初始段的突触后受体结合。由于GAD67和reelin在精神分裂症中下调,提示精神分裂症患者可能表达gaba能缺陷相关的锥体神经元功能改变。在精神分裂症患者的前额叶皮层中发现树突棘减少。由于树突棘受谷氨酸能轴突末梢的支配,这种树突棘表达的减少很可能转化为谷氨酸能传递的功能缺陷。神经元回路的可塑性修饰可能依赖于gaba能递质音调,gaba能功能障碍可能是精神分裂症突触可塑性缺陷的根源。因此,治疗精神分裂症的一个可能途径是利用GABA作用于GABAA受体的正变构调节剂来解决这种GABA能功能缺陷。苯二氮卓类药物(BZ)如地西泮对治疗精神分裂症的阳性和阴性症状有效,但由于它们正向调节表达α 1亚基的GABAA受体,这些BZ引起镇静和耐受性。相反,咪唑尼是表达alpha5亚基的GABAA受体的完全变构调节剂,可以在不产生镇静的情况下减轻精神病症状。因此,咪唑尼应该作为精神分裂症药物干预的潜在候选药物进行适当的研究。
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A GABAergic cortical deficit dominates schizophrenia pathophysiology.

Several lines of evidence support the role of an epigenetic-induced GABAergic cortical dysfunction in schizophrenia psychopathology, which is probably dependent on an increase in the expression of DNA-methyltransferase-1 occurring selectively in GABAergic neurons. The key enzyme regulating GABA synthesis, termed glutamic acid decarboxylase 67 (GAD67) and the important neurodevelopmental protein called reelin are coexpressed in GABAergic neurons. Upon release, GABA and reelin bind to postsynaptic receptors located in dendrites, somata, or the axon initial segment of pyramidal neurons. Because GAD67 and reelin are downregulated in schizophrenia, it is suggested that schizophrenics may express GABAergic deficit-related alterations of pyramidal neuron function. A reduction of dendritic spines is a finding reported in the prefrontal cortex of schizophrenia patients. Because dendritic spines are innervated by glutamatergic axon terminals, very probably this reduction of dendritic spine expression is translated into a functional deficit of glutamatergic transmission. Plastic modifications of neuronal circuits are probably dependent on GABAergic transmitter tone, and it is likely that GABAergic dysfunction is at the root of synaptic plasticity deficits in schizophrenia. Thus, a possible avenue for the treatment of schizophrenia would be to address this GABAergic functional deficit using positive allosteric modulators of the action of GABA at GABAA receptors. Benzodiazepines (BZ) such as diazepam are effective in treating positive and negative symptoms of schizophrenia, but because they positively modulate GABAA receptors expressing alpha1 subunits, these BZs cause sedation and tolerance. In contrast, imidazenil, a full allosteric modulator of GABAA receptors expressing alpha5 subunits may reduce psychotic symptomatology without producing sedation. Hence, imidazenil should be appropriately studied as a prospective candidate for a pharmacological intervention in schizophrenia.

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