MRC London Institute of Medical Sciences (LMS), Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK.
Sci Rep. 2017 Jul 12;7(1):5248. doi: 10.1038/s41598-017-05578-5.
Dopamine neurons in the substantia nigra pars compacta and ventral tegmental area regulate behaviours such as reward-related learning, and motor control. Dysfunction of these neurons is implicated in Schizophrenia, addiction to drugs, and Parkinson's disease. While some dopamine neurons fire single spikes at regular intervals, others fire irregular single spikes interspersed with bursts. Pharmacological inhibition of calcium-activated potassium (SK) channels increases the variability in their firing pattern, sometimes also increasing the number of spikes fired in bursts, indicating that SK channels play an important role in maintaining dopamine neuron firing regularity and burst firing. However, the exact mechanisms underlying these effects are still unclear. Here, we develop a biophysical model of a dopamine neuron incorporating ion channel stochasticity that enabled the analysis of availability of ion channels in multiple states during spiking. We find that decreased firing regularity is primarily due to a significant decrease in the AHP that in turn resulted in a reduction in the fraction of available voltage-gated sodium channels due to insufficient recovery from inactivation. Our model further predicts that inhibition of SK channels results in a depolarisation of action potential threshold along with an increase in its variability.
黑质致密部和腹侧被盖区的多巴胺神经元调节奖赏相关学习和运动控制等行为。这些神经元的功能障碍与精神分裂症、药物成瘾和帕金森病有关。虽然一些多巴胺神经元以规则的间隔发射单个尖峰，但其他神经元发射不规则的单个尖峰，其间穿插着爆发。钙激活钾 (SK) 通道的药理学抑制增加了它们的发射模式的可变性，有时也增加了爆发中发射的尖峰数量，表明 SK 通道在维持多巴胺神经元发射规则性和爆发发射方面发挥着重要作用。然而，这些影响的确切机制仍不清楚。在这里，我们开发了一个包含离子通道随机性的多巴胺神经元的生物物理模型，该模型能够在尖峰过程中分析多个状态下离子通道的可用性。我们发现，放电规则性的降低主要是由于 AHP 显著降低，这反过来又由于失活恢复不足导致电压门控钠离子通道的可用分数减少。我们的模型进一步预测，SK 通道的抑制会导致动作电位阈值去极化，同时其可变性增加。
