Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy.
Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy.
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DOI：
10.1016/j.expneurol.2010.01.021
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发表时间：
2010-06
影响因子：
5.3
通讯作者：
Smith, Bret N.
中科院分区：
文献类型：
--
作者：
Bhaskaran, Muthu D.;Smith, Bret N.
颞叶癫痫(TLE)是一种以颞叶兴奋和抑制失衡为特征的疾病。这种变化的特点是轴突萌发和伴随而来的是颞叶的突触重组。合成和内源性大麻素在治疗难治性颞叶癫痫方面具有不同的治疗潜力，部分原因是大麻素配体可以结合多种受体类型。本研究利用体外电生理学方法，观察了海马齿状回颗粒细胞中瞬时受体电位香草酸1型(TRPV1)的激活对TLE小鼠模型的影响。辣椒素是一种选择性的TRPV1激动剂，对对照动物颗粒细胞的突触输入没有明显影响，但显著增加了TLE小鼠的自发和微型EPSC频率。外源应用阿南达胺，一种同时作用于TRPV1和大麻素1型受体(CB1R)的内源性大麻素，也可以在CB1R拮抗剂存在的情况下促进谷氨酸的释放。卡萨西平阻断TRPV1时，阿南达胺使EPSC频率降低。对TRPV1受体的Western印迹分析表明，TLE小鼠齿状回中的蛋白表达明显高于对照组。这项研究表明，一种重要的大麻类激动剂可以通过激活TRPV1受体，增加TLE小鼠突触重组齿状回的兴奋回路活动，并建议在设计基于调节内源性大麻系统的抗惊厥治疗时应谨慎。
Temporal lobe epilepsy (TLE) is a condition characterized by an imbalance between excitation and inhibition in the temporal lobe. Hallmarks of this change are axon sprouting and accompanying synaptic reorganization in the temporal lobe. Synthetic and endogenous cannabinoids have variable therapeutic potential in treating intractable temporal lobe epilepsy, in part because cannabinoid ligands can bind multiple receptor types. This study utilized in vitro electrophysiological methods to examine the effect of transient receptor potential vanilloid type 1 (TRPV1) activation in dentate gyrus granule cells in a murine model of TLE. Capsaicin, a selective TRPV1 agonist had no measurable effect on overall synaptic input to granule cells in control animals, but significantly enhanced spontaneous and miniature EPSC frequency in mice with TLE. Exogenous application of anandamide, an endogenous cannabinoid that acts at both TRPV1 and cannabinoid type 1 receptors (CB1R), also enhanced glutamate release in the presence of a CB1R antagonist. Anandamide reduced the EPSC frequency when TRPV1 were blocked with capsazepine. Western blot analysis of TRPV1 receptor indicated protein expression was significantly greater in the dentate gyrus of mice with TLE compared with control mice. This study indicates that a prominent cannabinoid agonist can increase excitatory circuit activity in the synaptically reorganized dentate gyrus of mice with TLE by activating TRPV1 receptors, and suggests caution in designing anticonvulsant therapy based on modulating the endocannabinoid system.
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影响因子：
5.3
作者：
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