Neuropsychiatric Phenotypes Produced by GABA Reduction in Mouse Cortex and Hippocampus.
Neuropsychiatric Phenotypes Produced by GABA Reduction in Mouse Cortex and Hippocampus.
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DOI：
10.1038/npp.2017.296
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Nakazawa K
中科院分区：
文献类型：
--
作者：
Kolata SM;Nakao K;Jeevakumar V;Farmer-Alroth EL;Fujita Y;Bartley AF;Jiang SZ;Rompala GR;Sorge RE;Jimenez DV;Martinowich K;Mateo Y;Hashimoto K;Dobrunz LE;Nakazawa K
尽管在精神分裂症和抑郁症中始终观察到皮质GAD 67减少和随后的GABA水平降低，但仍不清楚这些GABA能异常如何导致特定症状。我们在小鼠中建立了皮质GAD 67减少的模型，其中Gad 1基因从约50%的皮质和海马中间神经元中被基因消融。突变小鼠表现出海马和皮质（包括mPFC）中组织GABA的减少，并表现出一系列基于努力的行为缺陷，包括在尾部悬挂和强迫游泳测试中减少的笼轮跑步和增加的不动性。由于糖精偏好、对食物反应的渐进比率和习得性无助任务均正常，因此，这种厌恶样行为不能用快感缺乏或行为绝望来解释。与前扣带皮层（ACC）中的多巴胺在评估参与行动的努力成本中发挥作用的流行观点一致，我们发现尾部悬挂触发了对照组ACC中的多巴胺释放，这在突变小鼠中严重减弱。相反，ACC多巴胺释放的渐进比例响应奖励，在此期间，动物被允许毫不费力地执行鼻子戳，不受影响的突变体。这些结果表明，皮质GABA减少优先损害的努力为基础的行为，需要付出很多努力，几乎没有好处，通过赤字的ACC多巴胺释放引发的高努力的成本行为，但不是由寻求奖励的行为。总的来说，精神分裂症和抑郁症患者中经常观察到的一部分阴性症状，其花费昂贵努力的意愿降低，可能归因于皮质GABA水平降低。
Whereas cortical GAD67 reduction and subsequent GABA level decrease are consistently observed in schizophrenia and depression, it remains unclear how these GABAergic abnormalities contribute to specific symptoms. We modeled cortical GAD67 reduction in mice, in which the Gad1 gene is genetically ablated from ~50% of cortical and hippocampal interneurons. Mutant mice showed a reduction of tissue GABA in the hippocampus and cortex including mPFC, and exhibited a cluster of effort-based behavior deficits including decreased home-cage wheel running and increased immobility in both tail suspension and forced swim tests. Since saccharine preference, progressive ratio responding to food, and learned helplessness task were normal, such avolition-like behavior could not be explained by anhedonia or behavioral despair. In line with the prevailing view that dopamine in anterior cingulate cortex (ACC) plays a role in evaluating effort cost for engaging in actions, we found that tail-suspension triggered dopamine release in ACC of controls, which was severely attenuated in the mutant mice. Conversely, ACC dopamine release by progressive ratio responding to reward, during which animals were allowed to effortlessly perform the nose-poking, was not affected in mutants. These results suggest that cortical GABA reduction preferentially impairs the effort-based behavior which requires much effort with little benefit, through a deficit of ACC dopamine release triggered by high-effort cost behavior, but not by reward-seeking behavior. Collectively, a subset of negative symptoms with a reduced willingness to expend costly effort, often observed in patients with schizophrenia and depression, may be attributed to cortical GABA level reduction.
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