A modeling study suggests complementary roles for GABAA and NMDA receptors and the SK channel in regulating the firing pattern in midbrain dopamine neurons
A modeling study suggests complementary roles for GABAA and NMDA receptors and the SK channel in regulating the firing pattern in midbrain dopamine neurons
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DOI：
10.1152/jn.00062.2003
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发表时间：
2004-01-01
影响因子：
2.5
通讯作者：
Canavier, CC
中科院分区：
文献类型：
--
作者：
Komendantov, AO;Komendantova, OG;Canavier, CC
中脑多巴胺能神经元在体内表现出两种主要的放电模式：单棘放电和爆发放电。所表达的放电模式依赖于神经元的固有特性及其兴奋性和抑制性突触输入。实验数据表明，N-甲基-D-天冬氨酸（NMDA）和GABA（A）受体的激活分别是爆发放电的启动和抑制的关键因素，阻断Ca 2+激活的钾SK通道可以促进爆发放电。建立了一个具有分支结构的DA神经元的多室模型，并基于体外实验数据进行了校准，以探讨不同水平的NMDA和GABA（A）受体激活以及SK电流调制对放电活动的影响。通过考虑体内与体外电紧张性质的差异来校准GABA（A）受体的模拟紧张激活。虽然NMDA诱发的电流是该模型中爆发产生所必需的，但GABA（A）受体激活诱发的电流也可以调节放电模式。例如，该模型预测，增加NMDA受体激活水平可产生过度去极化，从而防止爆发性放电，但同时增加GABA（A）受体的激活可恢复爆发性放电。该模型的另一个预测是，在体内阻断SK通道电流将促进爆发，但不如阻断GABA（A）受体那样稳健。
Midbrain dopaminergic (DA) neurons in vivo exhibit two major firing patterns: single-spike firing and burst firing. The firing pattern expressed is dependent on both the intrinsic properties of the neurons and their excitatory and inhibitory synaptic inputs. Experimental data suggest that the activation of N-methyl-D-aspartate (NMDA) and GABA(A) receptors is a crucial contributor to the initiation and suppression of burst firing, respectively, and that blocking Ca2+-activated potassium SK channels can facilitate burst firing. A multi-compartmental model of a DA neuron with a branching structure was developed and calibrated based on in vitro experimental data to explore the effects of different levels of activation of NMDA and GABA(A) receptors as well as the modulation of the SK current on the firing activity. The simulated tonic activation of GABA(A) receptors was calibrated by taking into account the difference in the electrotonic properties in vivo versus in vitro. Although NMDA-evoked currents are required for burst generation in the model, currents evoked by GABA(A)-receptor activation can also regulate the firing pattern. For example, the model predicts that increasing the level of NMDA receptor activation can produce excessive depolarization that prevents burst firing, but a concurrent increase in the activation of GABA(A) receptors can restore burst firing. Another prediction of the model is that blocking the SK channel current in vivo will facilitate bursting, but not as robustly as blocking the GABA(A) receptors.