Knowlton Christopher, Kutterer Sylvie, Roeper Jochen, Canavier Carmen C
Department of Cell Biology and Anatomy, Louisiana State University Health Sciences Center , New Orleans, Louisiana.
Institut für Neurophysiologie, Goethe University , Frankfurt , Germany.
J Neurophysiol. 2018 Jan 1;119(1):84-95. doi: 10.1152/jn.00351.2017. Epub 2017 Oct 4.
Burst firing in medial substantia nigra (mSN) dopamine (DA) neurons has been selectively linked to novelty-induced exploration behavior in mice. Burst firing in mSN DA neurons, in contrast to lateral SN DA neurons, requires functional ATP-sensitive potassium (K-ATP) channels both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is unknown. We show experimentally that L-type calcium channel activity in mSN DA neurons enhances open probability of K-ATP channels. We then generate a mathematical model to study the role of Ca dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca influx leads to local accumulation of ADP due to Ca-ATPase activity, which in turn activates K-ATP channels. If K-ATP channel activation reaches levels sufficient to terminate spiking, rhythmic bursting occurs. The model explains the experimental observation that, in vitro, coapplication of NMDA and a selective K-ATP channel opener, NN414, is required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca influx, which increases the activation of K-ATP. The model suggests that additional sources of hyperpolarization, such as GABAergic synaptic input, are recruited in vivo for burst termination or rebound burst discharge. The model predicts that NN414 increases the sensitivity of the K-ATP channel to ADP, promoting burst firing in vitro, and that that high levels of Ca buffering, as might be expected in the calbindin-positive SN DA neuron subpopulation, promote rhythmic bursting pattern, consistent with experimental observations in vivo. NEW & NOTEWORTHY Recently identified distinct subpopulations of midbrain dopamine neurons exhibit differences in their two primary activity patterns in vivo: tonic (single spike) firing and phasic bursting. This study elucidates the biophysical basis of bursts specific to dopamine neurons in the medial substantia nigra, enabled by ATP-sensitive K channels and necessary for novelty-induced exploration. A better understanding of how dopaminergic signaling differs between subpopulations may lead to therapeutic strategies selectively targeted to specific subpopulations.
内侧黑质（mSN）多巴胺（DA）神经元的爆发式放电已被选择性地与小鼠的新奇诱导探索行为联系起来。与外侧黑质DA神经元相比，mSN DA神经元的爆发式放电在体外和体内都需要功能性的ATP敏感性钾（K-ATP）通道。然而，K-ATP通道在促进爆发式放电中的确切作用尚不清楚。我们通过实验表明，mSN DA神经元中的L型钙通道活性增强了K-ATP通道的开放概率。然后，我们建立了一个数学模型来研究在爆发过程中驱动mSN DA神经元中K-ATP通道功能的钙动力学的作用。在我们的模型中，钙内流由于钙-ATP酶的活性导致ADP的局部积累，进而激活K-ATP通道。如果K-ATP通道的激活达到足以终止动作电位发放的水平，就会发生节律性爆发。该模型解释了以下实验观察结果：在体外，需要同时应用NMDA和一种选择性K-ATP通道开放剂NN414才能引发爆发。模拟的NMDA受体激活增加了放电频率和钙内流速率，从而增加了K-ATP的激活。该模型表明，在体内会募集额外的超极化来源，如GABA能突触输入，用于爆发终止或反弹爆发放电。该模型预测，NN414增加了K-ATP通道对ADP的敏感性，在体外促进爆发式放电，并且正如在钙结合蛋白阳性的黑质DA神经元亚群中预期的那样，高水平的钙缓冲促进节律性爆发模式，这与体内实验观察结果一致。新发现与值得注意的是最近确定的中脑多巴胺神经元的不同亚群在其体内两种主要活动模式上存在差异：紧张性（单个动作电位）发放和相位性爆发。本研究阐明了内侧黑质中多巴胺神经元特有的爆发的生物物理基础，这是由ATP敏感性钾通道实现的，并且是新奇诱导探索所必需的。更好地理解亚群之间多巴胺能信号传导的差异可能会导致针对特定亚群的选择性治疗策略。
