Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area
Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area
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DOI：
10.1073/pnas.1500450112
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发表时间：
2015-03-24
影响因子：
11.1
通讯作者：
Simpson, Eleanor H.
中科院分区：
文献类型：
--
作者：
Krabbe, Sabine;Duda, Johanna;Simpson, Eleanor H.
有强有力的证据表明，精神分裂症的核心缺陷是多巴胺(DA)系统功能障碍造成的，但这种功能障碍的细节仍不清楚。我们之前报道了一种转基因小鼠模型，该模型选择性和可逆地在纹状体内过度表达DA D2受体(D2R-OE小鼠)。D2R-OE小鼠表现出认知和动机缺陷，这与精神分裂症患者观察到的认知和动机缺陷惊人地相似。在此，我们发现在体内，D2R-OE小鼠中脑DA神经元的放电频率(紧张性活动)和爆发性放电(时相活动)都在腹侧被盖区(VTA)受到损害，但在黑质(SN)没有受到损害。通过在成年期切断转基因使纹状体D2R活动正常化，恢复了VTA DA神经元紧张性活动的减少，这与我们先前在我们的模型中报道的动机拯救是一致的。另一方面，突发性活动的减少并未得到挽救，这可能反映在D2R-OE小鼠中观察到的认知缺陷的持久性。我们已经确定了D2R-OE小鼠DA VTA神经元活性改变的一个潜在的分子机制：在已鉴定的中脑边缘DA VTA神经元中选择性地减少了不同的NMDA受体亚单位的表达，但在黑质纹状体DA SN神经元中没有。这些结果表明，与精神分裂症症状相关的功能缺陷可能涉及对选择性DA通路的不同调节。
There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.