Differential modulation of respiratory neuronal discharge patterns by GABAA receptor and apamin-sensitive K+ channel antagonism
Differential modulation of respiratory neuronal discharge patterns by GABAA receptor and apamin-sensitive K+ channel antagonism
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DOI：
10.1152/jn.2001.86.5.2363
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发表时间：
2001-11-01
影响因子：
2.5
通讯作者：
Zuperku, EJ
中科院分区：
文献类型：
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作者：
Tonkovic-Capin, V;Stucke, AG;Zuperku, EJ
尾侧腹侧呼吸组（cVRG）的呼吸神经元放电模式似乎受强gaba能增益调制的影响。局部应用GABA(A)受体拮抗剂甲氯双库兰可放大内源性兴奋性和抑制性突触输入介导的潜在放电频率（F-n）模式。增益调制也可以通过阿帕胺敏感的小电导Ca2+激活的K+ (SK)通道介导的超极化（AHPs）后尖峰振幅的改变而产生。由于双管碱（BICm）的甲基衍生物也被证明可以降低ahp的振幅，在体外，BICm诱导的增益调制可能是由于SK通道的阻塞。这些研究的目的是确定BICm产生增益调制的机制，并表征SK通道在控制呼吸神经元放电中的影响。本研究在失智、瘫痪、通气犬的cVRG吸气(I)和呼气(E)神经元的体内研究中采用了六种方案。该方案包括表征神经元对1)BICm和apamin在同一神经元上的反应，2)BICm在最大apamin诱导的ahp阻滞期间，3)apamin在最大BICm诱导的增益调节反应期间，4)特异性GABA（A)受体拮抗剂，（1)β -水合碱，5）特异性GABA(A)受体激动剂muscimol， 6） GABA摄取抑制剂nipecotic酸。对于方案3、5和6，只研究了E神经元。采用四管微移液管进行细胞外单神经元记录和药物压射。周期触发直方图用于量化F-n模式，并确定药物引起的F-n模式的增益（斜率）和偏移量的变化。与最大有效剂量率下的维生素a相比，BICm的峰值F-n增加了2.1倍，平均F-n增加了3.1倍。BICm和维生素a产生了相似的增重，但由于维生素a的抵消更负。对水合肼的反应与BICm相似。在最大的维生素a阻断期间，BICm产生了额外的112 +/- 22%的峰值F-n增加。相反，在bicm诱导的最大反应期间，apamin产生了额外的176 +/- 74%的峰F-n增加。麝香酚和尼柏乙酸都降低了放电模式的增益和偏移。综上所述，这些结果表明，BICm的增益调节作用是由于GABA(a)-能量分流抑制的减少，而不是通过阻断犬cVRG神经元中的SK通道来减少ahp。
The discharge patterns of respiratory neurons of the caudal ventral respiratory group (cVRG) appear to be subject to potent GABAergic gain modulation. Local application of the GABA(A) receptor antagonist bicuculline methochloride amplifies the underlying discharge frequency (F-n) patterns mediated by endogenous excitatory and inhibitory synaptic inputs. Gain modulation can also be produced by alterations in the amplitude of spike afterhyperpolarizations (AHPs) mediated by apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels. Since methyl derivatives of bicuculline (BICm) also have been shown to reduce the amplitude of AHPs, in vitro, it is possible that the BICm-induced gain modulation is due to a block of SK channels. The purpose of these studies was to determine the mechanisms by which BICm produces gain modulation and to characterize the influence of SK channels in the control of respiratory neuron discharge. Six protocols were used in this in vivo study of cVRG inspiratory (I) and expiratory (E) neurons in decerebrate, paralyzed, ventilated dogs. The protocols included characterizations of the neuronal responses to 1) BICm and apamin on the same neuron, 2) BICm during maximum apamin-induced block of AHPs, 3) apamin during maximum BICm-induced gain modulatory responses, 4) the specific GABA(A) receptor antagonist, (1) beta -hydrastine, 5) the specific GABA(A) receptor agonist, muscimol, and 6) the GABA uptake inhibitor, nipecotic acid. For protocols 3, 5, and 6, only E neurons were studied. Four-barrel micropipettes were used for extracellular single neuron recording and pressure ejection of drugs. Cycle-triggered histograms were used to quantify the F-n patterns and to determine the drug-induced changes in the gain (slope) and offset of the F-n patterns. Compared to apamin at maximum effective dose rates, BICm produced a 2.1-fold greater increase in peak F-n and a 3.1-fold greater increase in average F-n. BICm and apamin produced similar increases in gain, but the offsets due to apamin were more negative. The responses to hydrastine were similar to BICm. During maximum apamin block, BICm produced an additional 112 +/- 22% increase in peak F-n. Conversely, apamin produced an additional 176 +/- 74% increase in peak F-n during the maximum BICm-induced response. Muscimol and nipecotic acid both decreased the gain and offset of the discharge patterns. Taken together, these results suggest that the gain modulatory effect of BICm is due to a reduction of GABA(A)-ergic shunting inhibition rather than a reduction in AHPs by block of SK channels in canine cVRG neurons.