Fernández de Sevilla David, Garduño Julieta, Galván Emilio, Buño Washington
Instituto Cajal, Consejo Superior de Investigaciones Científicas, Av. Dr. Arce 37, 28002 Madrid, Spain.
J Neurophysiol. 2006 Dec;96(6):3028-41. doi: 10.1152/jn.00434.2006. Epub 2006 Sep 13.
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 Ca(2+)-activated K(+)-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg(2+)-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 KMeSO(4) 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.
钙激活钾电导调节神经元兴奋性，但其在癫痫发生中的作用仍不清楚。我们在大鼠CA3锥体神经元中研究了Ca(2+)激活的K(+)介导的超极化后电位（AHPs）在无镁林格液中由4-氨基吡啶（4-AP）体外诱导的癫痫样活动的发生和调节中的作用。产生了由延长的AHPs终止的反复出现的棘波爆发。配对记录中CA3锥体神经元之间的爆发同步是这种发作间期样活动的典型特征。中等超极化后电位（mAHP）的下调与发作间期样活动的出现平行。当用蜂毒明肽降低或增强mAHP时，4-AP诱导的爆发分别增加或受阻。用卡巴胆碱、t-ACPD或异丙肾上腺素抑制慢超极化后电位（sAHP）会增加爆发频率并破坏锥体神经元对之间爆发的规律性和同步性。相反，用KMeSO(4)进行细胞内透析增强sAHP会降低爆发频率。阻断GABA(A-B)抑制作用不会改变异常活动。我们描述了新的细胞机制，其中1）抑制mAHP通过减少负反馈在爆发活动的发生和调节中起重要作用，2）sAHP通过降低兴奋性来设定爆发间隔，3）爆发通过兴奋性突触相互作用同步，这种相互作用在爆发前和爆发期间增加，在随后的整个sAHP期间减少。这些细胞机制在癫痫样活动起始的CA3区域活跃，并协同调节同步节律性发作间期样网络活动的时间。
