Kozhemyakin Maxim, Rajasekaran Karthik, Kapur Jaideep
Dept. of Neurology, University of Virginia-HSC, Charlottesville, VA 22908, USA.
J Neurophysiol. 2010 Apr;103(4):1748-57. doi: 10.1152/jn.00949.2009. Epub 2010 Jan 27.
Central cholinergic overstimulation results in prolonged seizures of status epilepticus in humans and experimental animals. Cellular mechanisms of underlying seizures caused by cholinergic stimulation remain uncertain, but enhanced glutamatergic transmission is a potential mechanism. Paraoxon, an organophosphate cholinesterase inhibitor, enhanced glutamatergic transmission on hippocampal granule cells synapses by increasing the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in a concentration-dependent fashion. The amplitude of mEPSCs was not increased, which suggested the possibility of enhanced action potential-dependent release. Analysis of EPSCs evoked by minimal stimulation revealed reduced failures and increased amplitude of evoked responses. The ratio of amplitudes of EPSCs evoked by paired stimuli was also altered. The effect of paraoxon on glutamatergic transmission was blocked by the muscarinic antagonist atropine and partially mimicked by carbachol. The nicotinic receptor antagonist α -bungarotoxin did not block the effects of paraoxon; however, nicotine enhanced glutamatergic transmission. These studies suggested that cholinergic overstimulation enhances glutamatergic transmission by enhancing neurotransmitter release from presynaptic terminals.
中枢胆碱能过度刺激会导致人类和实验动物出现癫痫持续状态的长时间发作。胆碱能刺激引发潜在癫痫发作的细胞机制尚不清楚，但谷氨酸能传递增强是一种潜在机制。对氧磷，一种有机磷酸酯胆碱酯酶抑制剂，通过以浓度依赖的方式增加自发兴奋性突触后电流（sEPSCs）的频率和幅度，增强了海马颗粒细胞突触上的谷氨酸能传递。微小兴奋性突触后电流（mEPSCs）的幅度没有增加，这表明存在增强的动作电位依赖性释放的可能性。对最小刺激诱发的兴奋性突触后电流（EPSCs）的分析显示失败次数减少，诱发反应幅度增加。配对刺激诱发的EPSCs幅度比也发生了改变。对氧磷对谷氨酸能传递的作用被毒蕈碱拮抗剂阿托品阻断，并被卡巴胆碱部分模拟。烟碱受体拮抗剂α-银环蛇毒素不阻断对氧磷的作用；然而，尼古丁增强了谷氨酸能传递。这些研究表明，胆碱能过度刺激通过增强突触前终末的神经递质释放来增强谷氨酸能传递。
