Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors.
Regulation of epileptiform activity by two distinct subtypes of extrasynaptic GABAA receptors.
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DOI：
10.1186/1756-6606-6-21
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发表时间：
2013-05-01
期刊：
影响因子：
3.6
通讯作者：
Chen G
中科院分区：
文献类型：
--
作者：
Sun Y;Wu Z;Kong S;Jiang D;Pitre A;Wang Y;Chen G
gaba能缺陷是癫痫发作的主要机制之一。以往的研究主要集中在癫痫发生过程中突触gaba能抑制的改变。最近的研究表明，强直性抑制也可能在调节癫痫发生中发挥作用，但其潜在机制尚不清楚。我们采用分子和药理学手段研究强直抑制在体外和体内癫痫发生中的作用。我们在培养的海马神经元中过表达两种不同亚型的突触外GABAA受体α5β3γ2和α6β3δ受体。我们证明α5β3γ2和α6β3δ受体的过表达在体外增强强直抑制和降低癫痫样活性。结果表明，大鼠脑内注射低浓度的选择性GABAA受体激动剂THIP （5 μM）也能抑制体内癫痫样爆发活动和行为性癫痫发作。在机制上，我们发现低浓度的THIP对gaba能突触传递没有影响，也不影响动作电位的基础水平，但明显抑制癫痫药物诱导的高频神经元活动。我们的研究表明，突触外GABAA受体在控制高兴奋性活动中发挥重要作用，例如在癫痫发生过程中，但在调节低水平的基础活动方面的作用不太突出。我们认为，在病理条件下，强直抑制可能比生理条件下在调节神经网络活动方面发挥更大的作用。
GABAergic deficit is one of the major mechanisms underlying epileptic seizures. Previous studies have mainly focused on alterations of synaptic GABAergic inhibition during epileptogenesis. Recent work suggested that tonic inhibition may also play a role in regulating epileptogenesis, but the underlying mechanism is not well understood. We employed molecular and pharmacological tools to investigate the role of tonic inhibition during epileptogenesis both in vitro and in vivo. We overexpressed two distinct subtypes of extrasynaptic GABAA receptors, α5β3γ2 and α6β3δ receptors, in cultured hippocampal neurons. We demonstrated that overexpression of both α5β3γ2 and α6β3δ receptors enhanced tonic inhibition and reduced epileptiform activity in vitro. We then showed that injection of THIP (5 μM), a selective agonist for extrasynaptic GABAA receptors at low concentration, into rat brain also suppressed epileptiform burst activity and behavioral seizures in vivo. Mechanistically, we discovered that low concentration of THIP had no effect on GABAergic synaptic transmission and did not affect the basal level of action potentials, but significantly inhibited high frequency neuronal activity induced by epileptogenic agents. Our studies suggest that extrasynaptic GABAA receptors play an important role in controlling hyperexcitatory activity, such as that during epileptogenesis, but a less prominent role in modulating a low level of basal activity. We propose that tonic inhibition may play a greater role under pathological conditions than in physiological conditions in terms of modulating neural network activity.
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影响因子：
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