Qiu Cuie, Zeyda Thomas, Johnson Brian, Hochgeschwender Ute, de Lecea Luis, Tallent Melanie K
Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19348, USA.
J Neurosci. 2008 Apr 2;28(14):3567-76. doi: 10.1523/JNEUROSCI.4679-07.2008.
The K(+) M-current (I(M), Kv7) is an important regulator of cortical excitability, and mutations in these channels cause a seizure disorder in humans. The neuropeptide somatostatin (SST), which has antiepileptic properties, augments I(M) in hippocampal CA1 pyramidal neurons. We used SST receptor knock-out mice and subtype-selective ligands to investigate the receptor subtype that couples to I(M) and mediates the antiepileptic effects of SST. Using pentylenetetrazole as a chemoconvulsant, SST(2), SST(3), and SST(4) receptor knock-out mice all had shorter latencies to different seizure stages and increased seizure severity when compared with wild-type mice. However, the most robust differences were observed in the SST(4) knock-outs. When seizures were induced by systemic injection of kainate, only SST(4) knock-outs showed an increase in seizure sensitivity. We next examined the action of SST and subtype-selective SST agonists on electrophysiological parameters in hippocampal slices of wild-type and receptor knock-out mice. SST(2) and SST(4) appear to mediate the majority of SST inhibition of epileptiform activity in CA1. SST lacked presynaptic effects in mouse CA1, in contrast to our previous findings in rat. SST increased I(M) in CA1 pyramidal neurons of wild-type and SST(2) knock-out mice, but not SST(4) knock-out mice. Using M-channel blockers, we found that SST(4) coupling to M-channels is critical to its inhibition of epileptiform activity. This is the first demonstration of an endogenous enhancer of I(M) that is important in controlling seizure activity. SST(4) receptors could therefore be an important novel target for developing new antiepileptic and antiepileptogenic drugs.
钾离子M电流(I(M),Kv7)是皮质兴奋性的重要调节因子,这些通道的突变会导致人类癫痫发作障碍。具有抗癫痫特性的神经肽生长抑素(SST)可增强海马CA1锥体神经元中的I(M)。我们使用SST受体敲除小鼠和亚型选择性配体来研究与I(M)偶联并介导SST抗癫痫作用的受体亚型。使用戊四氮作为化学惊厥剂,与野生型小鼠相比,SST(2)、SST(3)和SST(4)受体敲除小鼠在不同癫痫发作阶段的潜伏期均较短,且癫痫发作严重程度增加。然而,在SST(4)敲除小鼠中观察到的差异最为显著。当通过全身注射海藻酸诱导癫痫发作时,只有SST(4)敲除小鼠表现出癫痫敏感性增加。接下来,我们研究了SST和亚型选择性SST激动剂对野生型和受体敲除小鼠海马切片电生理参数的作用。SST(2)和SST(4)似乎介导了SST对CA1区癫痫样活动的大部分抑制作用。与我们之前在大鼠中的发现相反,SST在小鼠CA1区缺乏突触前效应。SST可增加野生型和SST(2)敲除小鼠CA1锥体神经元中的I(M),但不能增加SST(4)敲除小鼠中的I(M)。使用M通道阻滞剂,我们发现SST(4)与M通道的偶联对其抑制癫痫样活动至关重要。这是首次证明内源性I(M)增强剂在控制癫痫发作活动中具有重要作用。因此,SST(4)受体可能是开发新型抗癫痫和抗癫痫药物的重要新靶点。