Calcium-activated afterhyperpolarizations regulate synchronization and timing of epileptiform bursts in hippocampal CA3 pyramidal neurons
Calcium-activated afterhyperpolarizations regulate synchronization and timing of epileptiform bursts in hippocampal CA3 pyramidal neurons
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DOI：
10.1152/jn.00434.2006
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发表时间：
2006-12-01
影响因子：
2.5
通讯作者：
Buno, Washington
中科院分区：
文献类型：
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作者：
Fernandez de Sevilla, David;Garduno, Julieta;Buno, Washington
钙激活的钾电导调节神经元的兴奋性，但它们在癫痫发生中的作用仍然难以捉摸。我们在大鼠CA3区锥体神经元上研究了钙激活的钾离子介导的后超极化(AHPs)在4-氨基吡啶(4-AP)诱导的无镁Ringer癫痫样活动的发生和调节中的作用。由延长的AHP终止的反复的尖峰爆发被产生。配对记录中CA3锥体神经元之间的突发性同步是这种发作间歇性活动的典型特征。中后超极化(MAHP)的下调与发作间隔样活动的出现平行。阿帕明降低mAHP或增强mAHP时，4-AP诱发的兴奋性爆发分别增加或阻断。用卡巴胆碱、t-acpd或异丙肾上腺素抑制慢后超极化(SAHP)可增加爆发频率，扰乱锥体神经元对之间的爆发规律性和同步性。相反，用KMeSO4细胞内透析提高SAHP可减少猝发频率。阻断GABA(A-B)抑制不能改变异常活动。我们描述了新的细胞机制，其中1)mAHP的抑制通过减少负反馈在爆发活动的发生和调节中发挥重要作用，2)SAHP通过降低兴奋性来设定爆发间隔，3)爆发是通过兴奋性突触相互作用同步的，这种相互作用在爆发之前和爆发期间增加，并在随后的SAHP中减少。这些细胞机制在CA3区活跃，癫痫样活动在那里启动，并协同调节同步节律性发作间歇性网络活动的时间。
Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca2+-activated K+-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg2+-free Ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A downregulation of the medium afterhyperpolarization (mAHP) paralleled the emergence of the interictal-like activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow afterhyperpolarization (sAHP) with carbachol, t-ACPD, or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with KMeSO4 reduced burst frequency. Block of GABA(A-B) inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where 1) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, 2) the sAHP sets the interburst interval by decreasing excitability, and 3) bursting was synchronized by excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity.