A reduced susceptibility to chemoconvulsant stimulation in adenylyl cyclase 8 knockout mice.
A reduced susceptibility to chemoconvulsant stimulation in adenylyl cyclase 8 knockout mice.
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DOI：
10.1016/j.eplepsyres.2015.11.007
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发表时间：
2016-01
影响因子：
2.2
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Chen X;Dong G;Zheng C;Wang H;Yun W;Zhou X
腺苷酸环化酶（ACs）催化ATP合成cAMP， cAMP信号传导影响大量神经元过程。CNS中表达的Ca2+刺激腺苷酸环化酶8 （AC8）在突触可塑性、药物成瘾和乙醇敏感性以及慢性疼痛中发挥作用。本研究旨在探讨AC8在癫痫发生中的作用。在本研究中，我们观察了kainic酸（20mg/kg或30mg/kg）或pilocarpine （350mg/kg）对AC8 KO和野生型小鼠的癫痫发作行为。接下来，我们注射kainic酸或pilocarpine诱导癫痫持续状态（SE），并在SE终止后24小时和2周分别检测海马神经元变性（氟玉B染色）和苔藓纤维发芽（Timm染色）。最后，腹腔注射kainic酸（30mg/kg） 15min后，我们用western blot和免疫化学染色检测海马磷酸化erk1 /2。我们首先观察到，AC8 KO突变体对两种化学惊厥药物，kainic酸和pilocarpine的易感性（包括癫痫发作潜伏期和发作次数）降低。此外，我们发现化学惊厥剂诱导的海马退行性神经元和苔藓纤维发芽显著减少。此外，western blot和免疫化学分析显示，kainic酸注射的AC8 KO小鼠海马区的MAPK信号被减弱。AC8参与癫痫发生，可能作为治疗癫痫的潜在靶点。
Adenylyl cyclases (ACs) catalyze the synthesis of cAMP from ATP, and cAMP signaling affects a large number of neuronal processes. Ca2+-stimualted adenylyl cyclase 8 (AC8) expressed in the CNS plays a role in synaptic plasticity, drug addiction and ethanol sensitivity, and chronic pain. This study was to aim at examining the contributions of AC8 to epileptogenesis. In this study, we observed the seizure behavior induced by kainic acid (20mg/kg or 30mg/kg) or pilocarpine (350mg/kg) in AC8 KO and wild-type mice. Next we injected kainic acid or pilocarpine to induce status epilepticus (SE), and examined neuronal degeneration (by Fluoro-Jade B staining) and mossy fiber sprouting (by Timm staining) 24 hr and 2 weeks after SE termination in the hippocampus, respectively. Finally, 15min after intraperitoneal injection of kainic acid (30mg/kg), we examined phosphor-ERK1/2 in the hippocampus by western blot and immunochemistry staining. We first observed that AC8 KO mutants display reduced susceptibility (including seizure latency and episodes) to two chemoconvulsants, kainic acid and pilocarpine. Moreover, we found that degenerative neurons and mossy fiber sprouting induced by chemoconvulsants were significant decreased in the hippocampus. Further, western blot and immunochemistry analysis revealed that the MAPK signaling in the hippocampus was attenuated in kainic acid-injected AC8 KO mice. AC8 is involved in epileptogenesis, and may serve as a potential target for the treatment of epilepsy.