Dynamic, nonlinear feedback regulation of slow pacemaking by A-type potassium current in ventral tegmental area neurons.
Dynamic, nonlinear feedback regulation of slow pacemaking by A-type potassium current in ventral tegmental area neurons.
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DOI：
10.1523/jneurosci.2237-08.2008
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发表时间：
2008-10-22
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影响因子：
--
通讯作者：
Bean BP
中科院分区：
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作者：
Khaliq ZM;Bean BP
我们分析了离子电流，调节小鼠腹侧被盖区多巴胺能神经元起搏比较电压轨迹自发放电与斜坡诱发电流电压钳。大多数记录都是在大脑切片中进行的，关键的实验使用急性分离的神经元重复进行，得到了相同的结果。在自发放电期间，从电压乘以细胞电容的时间导数计算尖峰之间流动的净离子电流，在许多放电循环上进行信号平均以提高分辨率。净内向峰间电流具有独特的非单调形状，在−60和−55 mV之间达到最小值（通常<1 pA）。在电压钳位下，亚阈值电压的斜坡引起了一个依赖于时间和电压的外向电流，峰值接近−55 mV。该电流在5 mV/s的斜坡下无法检测到，并且在自然起搏的典型范围（10 - 50 mV/s）内随着去极化率急剧增加。Ramp诱发的阈下电流对α-树毒素、paxilline、apamin和四乙铵具有抗性，但对4-氨基吡啶和0.5 mM Ba 2+敏感，与A型钾电流（IA）一致。不同斜坡速度与自然自发去极化引起的电流的同细胞比较表明，IA对去极化速率的陡峭依赖性如何导致起搏过程中的小净内向电流。这些结果揭示了一种机制，其中亚阈值IA在稳态下接近于零，但在去极化速率>10 mV/s时作为一个强大的超线性反馈元件。这种反馈机制解释了净离子电流如何被限制在<1-2 pA，但可靠地向内，从而实现缓慢，有规律的发射。
We analyzed ionic currents that regulate pacemaking in dopaminergic neurons of the mouse ventral tegmental area by comparing voltage trajectories during spontaneous firing with ramp-evoked currents in voltage clamp. Most recordings were made in brain slice, with key experiments repeated using acutely dissociated neurons, which gave identical results. During spontaneous firing, net ionic current flowing between spikes was calculated from the time derivative of voltage multiplied by cell capacitance, signal-averaged over many firing cycles to enhance resolution. Net inward interspike current had a distinctive nonmonotonic shape, reaching a minimum (generally <1 pA) between −60 and −55 mV. Under voltage clamp, ramps over subthreshold voltages elicited a time- and voltage-dependent outward current that peaked near −55 mV. This current was undetectable with 5 mV/s ramps and increased steeply with depolarization rate over the range (10 –50 mV/s) typical of natural pacemaking. Ramp-evoked subthreshold current was resistant to α-dendrotoxin, paxilline, apamin, and tetraethylammonium but sensitive to 4-aminopyridine and 0.5 mM Ba2+, consistent with A-type potassium current (IA). Same-cell comparison of currents elicited by various ramp speeds with natural spontaneous depolarization showed how the steep dependence of IA on depolarization rate results in small net inward currents during pacemaking. These results reveal a mechanism in which subthreshold IA is near zero at steady state, but is engaged at depolarization rates >10 mV/s to act as a powerful, supralinear feedback element. This feedback mechanism explains how net ionic current can be constrained to <1–2 pA but reliably inward, thus enabling slow, regular firing.