癫痫,经常与抑郁症共病,容易产生耐药性。这里,我们调查了背侧中缝(DR)及其5-HTergic神经元与癫痫的关系。
在小鼠海马点燃模型中,使用免疫化学,钙纤维光度法,光遗传学,我们调查了DR5-HT能神经元在颞叶癫痫(TLE)发作中的因果作用。Further,应用不同频率的DR深部脑刺激(DBS)来测试其对海马癫痫发作和抑郁样行为的影响。
在点燃引起的海马癫痫发作期间,DR中c-fos神经元的数量和DR5-HTergic神经元的钙活性均增加。光遗传学抑制,但不是激活,特别是在后期,DR5-HT能神经元明显阻碍了癫痫发作的获得。对于临床翻译,1Hz特定,但不是20赫兹或100赫兹,DR的DBS阻碍了海马癫痫发作的获得。这种治疗作用可能是通过抑制DR5-HT能神经元介导的,因为DR5-HT能神经元的光遗传学激活逆转了1-HzDRDBS的抗癫痫作用。然而,DBS治疗对抑郁样行为没有影响。
抑制DR5-HT能神经元的过度活跃可能具有有希望的抗癫痫作用,DR可能是治疗TLE的潜在DBS靶标。
Epilepsy, frequently comorbid with depression, easily develops drug resistance. Here, we investigated how dorsal raphe (DR) and its 5-HTergic neurons are implicated in epilepsy.
In mouse hippocampal kindling model, using immunochemistry, calcium fiber photometry, and optogenetics, we investigated the causal role of DR 5-HTergic neurons in seizure of temporal lobe epilepsy (TLE). Further, deep brain stimulation (DBS) of the DR with different frequencies was applied to test its effect on hippocampal seizure and depressive-like behavior.
Number of c-fos+ neurons in the DR and calcium activities of DR 5-HTergic neurons were both increased during kindling-induced hippocampal seizures. Optogenetic inhibition, but not activation, of DR 5-HTergic neurons conspicuously retarded seizure acquisition specially during the late period. For clinical translation, 1-Hz-specific, but not 20-Hz or 100-Hz, DBS of the DR retarded the acquisition of hippocampal seizure. This therapeutic effect may be mediated by the inhibition of DR 5-HTergic neurons, as optogenetic activation of DR 5-HTergic neurons reversed the anti-seizure effects of 1-Hz DR DBS. However, DBS treatment had no effect on depressive-like behavior.
Inhibition of hyperactivity of DR 5-HTergic neuron may present promising anti-seizure effect and the DR may be a potential DBS target for the therapy of TLE.