Synaptic activity unmasks dopamine D2 receptor modulation of a specific class of layer V pyramidal neurons in prefrontal cortex.
Synaptic activity unmasks dopamine D2 receptor modulation of a specific class of layer V pyramidal neurons in prefrontal cortex.
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DOI：
10.1523/jneurosci.5835-11.2012
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发表时间：
2012-04-04
期刊：
影响因子：
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通讯作者：
Sohal VS
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文献类型：
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作者：
Gee S;Ellwood I;Patel T;Luongo F;Deisseroth K;Sohal VS
多巴胺D2受体（D2Rs）在前额叶皮质（PFC）的功能中起着重要作用，并可能导致精神分裂症等疾病的前额叶功能障碍。在小鼠PFC中，D2Rs通过V层锥体神经元的一种亚型选择性表达，这种亚型具有较厚的顶端簇，突出的h电流和皮层下投射。在这个亚群中，D2R激动剂喹匹罗引发了一种新的后去极化，产生电压波动和数百毫秒的尖峰。令人惊讶的是，这种后去极化在静止的大脑切片中被掩盖，但很容易被激活NMDA受体的突触输入的生理水平所掩盖，这可能解释了为什么这种现象以前没有报道过。值得注意的是，在突触刺激停止后的一段时间内，我们仍然可以引起这种后去极化。除了NMDA受体外，喹匹罗诱导的后去极化也依赖于l型Ca2+通道，并被选择性l型拮抗剂尼莫地平阻断。为了证实D2Rs可以通过增强Ca2+（和Ca2+依赖性）电流来引发这种后去极化，我们测量了阻断Na+和K+通道后发生的全细胞Ca2+电位，发现喹匹罗增强了这些电位，而选择性D2R拮抗剂（−）磺胺吡啶具有相反的作用。因此，D2Rs可以引发Ca2+通道依赖的后去极化，从而有力地调节特定前额叶神经元的活动。通过这种机制，D2Rs可能会增强皮层下结构的输出，促进与奖励相关的持续放电，或者增加前额叶回路的噪音水平。
Dopamine D2 receptors (D2Rs) play a major role in the function of the prefrontal cortex (PFC), and may contribute to prefrontal dysfunction in conditions such as schizophrenia. Here we report that in mouse PFC, D2Rs are selectively expressed by a subtype of layer V pyramidal neurons that have thick apical tufts, prominent h-current, and subcortical projections. Within this subpopulation, the D2R agonist quinpirole elicits a novel afterdepolarization that generates voltage fluctuations and spiking for hundreds of milliseconds. Surprisingly, this afterdepolarization is masked in quiescent brain slices, but is readily unmasked by physiologic levels of synaptic input which activate NMDA receptors, possibly explaining why this phenomenon has not been reported previously. Notably, we could still elicit this afterdepolarization for some time after the cessation of synaptic stimulation. Besides NMDA receptors, the quinpirole-induced afterdepolarization also depended on L-type Ca2+ channels and was blocked by selective L-type antagonist nimodipine. To confirm that D2Rs can elicit this afterdepolarization by enhancing Ca2+ (and Ca2+-dependent) currents, we measured whole-cell Ca2+ potentials that occur after blocking Na+ and K+ channels, and found quinpirole enhanced these potentials, while the selective D2R antagonist (−)sulpiride had the opposite effect. Thus, D2Rs can elicit a Ca2+-channel dependent afterdepolarization that powerfully modulates activity in specific prefrontal neurons. Through this mechanism, D2Rs might enhance outputs to subcortical structures, contribute to reward related persistent firing, or increase the level of noise in prefrontal circuits.