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首页> 外文期刊>Physiological Reports >Regulating hippocampal hyperexcitability through GABAB Receptors
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Regulating hippocampal hyperexcitability through GABAB Receptors

机译：通过GABAB受体调节海马兴奋性

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AbstractDisturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein-coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 μmol/L nor the GABAB receptor agonist baclofen at 0.1 μmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 μmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure-related hyperexcitability.
机译：摘要GABA能抑制的干扰是癫痫性癫痫发作的主要原因。 GABA通过离子型GABAA受体和代谢型G蛋白偶联的GABAB受体发挥作用。早在癫痫发作中就已认识到GABAA抑制功能异常，但仍不清楚GABAB受体在控制癫痫发作活动中的作用。在这里，我们通过使用正变构型GABAB受体调节剂GS 39783和选择性GABAB受体拮抗剂CGP 55845来检查GABAB受体在小鼠海马点燃模型和海马切片中的抗惊厥或抑制作用。当通过腹腔注射对点燃的小鼠进行给药时，GS 39783（5 mg / kg）不会减弱海马EEG的排出量，但确实减少了海马的异常尖峰，而CGP 55845（10 mg / kg）延长了海马的排出量并增加了尖峰发生率。在海马切片中检查时，单独以5μmol/ L的GS 39783或单独以0.1μmol/ L的GABAB受体激动剂巴氯芬均不能显着改变重复性兴奋性场电位，但GS 39783和巴氯芬可逆地消除了这些场电位。相比之下，CGP 55845在1μmol/ L的情况下促进了这些场电位的感应和发生。此外，CGP 55845减弱了CA3群体尖峰的成对脉冲抑制，并增加了单个CA3锥体神经元中EPSC的频率。总体而言，这些数据表明，GABABB受体通过抑制CA3谷氨酸能突触来调节海马超兴奋性。我们推测，GABA B受体的正构构调节可能会有效减少癫痫发作相关的过度兴奋性。

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