Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia
Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia
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DOI：
10.1176/appi.ajp.2008.08101484
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发表时间：
2009-04-01
影响因子：
17.7
通讯作者：
Lewis, David A.
中科院分区：
文献类型：
--
作者：
Maldonado-Aviles, Jaime G.;Curley, Allison A.;Lewis, David A.
目的：精神分裂症的认知障碍与前额叶皮质中γ-氨基丁酸（GABA）合成标记物的低表达相关。GABA的作用由GABA（A）受体介导，该受体介导相位或强直抑制。作者评估了精神分裂症患者GABA（A）受体α 4和δ亚基的表达，这些亚基共同组装形成介导紧张性抑制的受体。方法：作者使用原位杂交技术定量了23对精神分裂症患者和对照受试者前额叶皮质中GABA（A）受体α 4和δ亚基的表达模式。结果：无论药物使用情况如何，精神分裂症受试者的Delta mRNA水平均显着较低，而仅在死亡时接受某些药物的精神分裂症受试者中α 4 mRNA水平较低。为了理解精神分裂症中α 4和δ亚基表达之间这种意想不到的分离的性质，作者使用类似的方法来定量多种动物模型中α 4和δ mRNA的水平。在出生后发育的猴前额叶皮层，α 4 mRNA水平下降，而δ mRNA水平上升。此外，在GABA（A）受体α 1亚基基因缺失的小鼠的内侧额叶皮层中，δ mRNA水平较低，而α 4 mRNA水平则没有变化，在兴奋性神经传递改变的啮齿动物模型中，δ和α 4 mRNA水平均未改变。由于GABA（A）受体α 1亚基在精神分裂症中的mRNA水平也较低，因此在猴子前额叶皮质中的表达随着年龄的增长而增加，并且可以与δ亚基共组装形成功能性GABA（A）受体，精神分裂症中较低的δ mRNA水平可能反映了α（1）β（x）δ GABA（A）受体数量的减少，这可能导致精神分裂症中缺乏紧张性抑制和前额叶皮质功能障碍。
Objective: Cognitive impairments in schizophrenia are associated with lower expression of markers of gamma-aminobutyric acid (GABA) synthesis in the prefrontal cortex. The effects of GABA are mediated by GABA(A) receptors that mediate either phasic or tonic inhibition. The authors assessed the expression of GABA(A) receptor alpha 4 and delta subunits, which coassemble to form receptors mediating tonic inhibition, in schizophrenia.Method: The authors used in situ hybridization to quantify expression patterns of GABA(A) receptor alpha 4 and delta subunits in prefrontal cortex from 23 matched pairs of schizophrenia and comparison subjects.Results: Levels of delta mRNA were significantly lower in schizophrenia subjects regardless of medication use, whereas alpha 4 mRNA levels were lower only in subjects with schizophrenia receiving certain medications at the time of death. To understand the nature of this unexpected dissociation between alpha 4 and delta subunit expression in schizophrenia, the authors used similar methods to quantify alpha 4 and delta mRNA levels in multiple animal models. During postnatal development of monkey prefrontal cortex, levels of alpha 4 mRNA decreased, whereas delta mRNA levels increased. In addition, delta mRNA levels, but not alpha 4 mRNA levels, were lower in the medial frontal cortex of mice with a genetic deletion of the GABA(A) receptor alpha 1 subunit, and neither delta nor alpha 4 mRNA levels were altered in rodent models of altered excitatory neurotransmission.Conclusions: Since GABA(A) receptor alpha 1 subunits also have lower mRNA levels in schizophrenia, show increased expression with age in monkey prefrontal cortex, and can coassemble with delta subunits to form functional GABA(A) receptors, lower delta mRNA levels in schizophrenia might reflect a reduced number of alpha(1)beta(x)delta GABA(A) receptors that could contribute to deficient tonic inhibition and prefrontal cortical dysfunction in schizophrenia.