Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy.
Cannabinoid-mediated inhibition of recurrent excitatory circuitry in the dentate gyrus in a mouse model of temporal lobe epilepsy.
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DOI：
10.1371/journal.pone.0010683
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发表时间：
2010-05-17
期刊：
影响因子：
3.7
通讯作者：
Smith BN
中科院分区：
文献类型：
--
作者：
Bhaskaran MD;Smith BN
颞叶癫痫(TLE)是一种与神经元丢失、轴突萌发和导致突触回路改变的海马区硬化相关的神经系统疾病。大麻素似乎在TLE患者和动物模型中具有抗惊厥作用，但这种作用的机制尚不清楚。采用匹罗卡品诱导的癫痫持续状态小鼠TLE模型，用电生理记录的方法研究了大麻素激动剂对正常小鼠和TLE小鼠海马片反复兴奋性环路的影响。大麻素激动剂Win 55,212-2，anandamide(AEA)或2-arachydonoylgarcerol(2-AG)可减少TLE小鼠自发的和河豚毒素抗性的兴奋性突触后电流(EPSCs)的频率，但在对照组没有。Win 55,212-2还降低了癫痫小鼠其他颗粒细胞谷氨酸光解激活诱发的EPSCs频率。反向电刺激门部苔藓纤维后诱发的次级群体放电也可被大麻素激动剂减弱。大麻素1型受体(CB1R)拮抗剂AM251可阻断激动剂的作用。没有经历癫痫持续状态的小鼠的切片中没有观察到谷氨酸释放的变化。Western印迹分析表明，TLE动物齿状回CB1R表达上调。这些结果表明，神经末梢上CB1R的激活可以抑制TLE小鼠齿状回的反复兴奋。这提示了大麻素的抗惊厥作用的机制，旨在调节癫痫发生后表达的突触终末上的受体。
Temporal lobe epilepsy (TLE) is a neurological condition associated with neuron loss, axon sprouting, and hippocampal sclerosis, which results in modified synaptic circuitry. Cannabinoids appear to be anti-convulsive in patients and animal models of TLE, but the mechanisms of this effect are not known. A pilocarpine-induced status epilepticus mouse model of TLE was used to study the effect of cannabinoid agonists on recurrent excitatory circuits of the dentate gyrus using electrophysiological recordings in hippocampal slices isolated from control mice and mice with TLE. Cannabinoid agonists WIN 55,212-2, anandamide (AEA), or 2-arachydonoylglycerol (2-AG) reduced the frequency of spontaneous and tetrodotoxin-resistant excitatory postsynaptic currents (EPSCs) in mice with TLE, but not in controls. WIN 55,212-2 also reduced the frequency of EPSCs evoked by glutamate-photolysis activation of other granule cells in epileptic mice. Secondary population discharges evoked after antidromic electrical stimulation of mossy fibers in the hilus were also attenuated by cannabinoid agonists. Agonist effects were blocked by the cannabinoid type 1 receptor (CB1R) antagonist AM251. No change in glutamate release was observed in slices from mice that did not undergo status epilepticus. Western blot analysis suggested an up-regulation of CB1R in the dentate gyrus of animals with TLE. These findings indicate that activation of CB1R present on nerve terminals can suppress recurrent excitation in the dentate gyrus of mice with TLE. This suggests a mechanism for the anti-convulsive role of cannabinoids aimed at modulating receptors on synaptic terminals expressed de novo after epileptogenesis.
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影响因子：
5.3
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