Xia Chen1, Guoying Dong1, Changhong Zheng1, Hongbing Wang2, Wenwei Yun3, Xianju Zhou4. 1. Laboratory of Neurological Diseases, Department of Neurology, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province 213003, China. 2. Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA. 3. Laboratory of Neurological Diseases, Department of Neurology, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province 213003, China. Electronic address: wenwei_yun@yahoo.com. 4. Laboratory of Neurological Diseases, Department of Neurology, Changzhou No. 2 People's Hospital, The Affiliated Hospital of Nanjing Medical University, Changzhou, Jiangsu Province 213003, China. Electronic address: xianju_zhou@yahoo.com.
Abstract
OBJECTIVE: Adenylyl cyclases (ACs) catalyze the synthesis of cAMP from ATP, and cAMP signaling affects a large number of neuronal processes. Ca(2+)-stimulated 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. METHODS: In this study, we observed the seizure behavior induced by kainic acid (20 mg/kg or 30 mg/kg) or pilocarpine (350 mg/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) 24h and 2 weeks after SE termination in the hippocampus, respectively. Finally, 15 min after intraperitoneal injection of kainic acid (30 mg/kg), we examined phosphor-ERK1/2 in the hippocampus by Western blot and immunochemistry staining. RESULTS: 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. CONCLUSION: AC8 is involved in epileptogenesis, and may serve as a potential target for the treatment of epilepsy.
OBJECTIVE: Adenylyl cyclases (ACs) catalyze the synthesis of cAMP from ATP, and cAMP signaling affects a large number of neuronal processes. Ca(2+)-stimulated 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. METHODS: In this study, we observed the seizure behavior induced by kainic acid (20 mg/kg or 30 mg/kg) or pilocarpine (350 mg/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) 24h and 2 weeks after SE termination in the hippocampus, respectively. Finally, 15 min after intraperitoneal injection of kainic acid (30 mg/kg), we examined phosphor-ERK1/2 in the hippocampus by Western blot and immunochemistry staining. RESULTS: 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. CONCLUSION:AC8 is involved in epileptogenesis, and may serve as a potential target for the treatment of epilepsy.
Authors: M L Schaefer; S T Wong; D F Wozniak; L M Muglia; J A Liauw; M Zhuo; A Nardi; R E Hartman; S K Vogt; C E Luedke; D R Storm; L J Muglia Journal: J Neurosci Date: 2000-07-01 Impact factor: 6.167
Authors: Y Watanabe; R S Johnson; L S Butler; D K Binder; B M Spiegelman; V E Papaioannou; J O McNamara Journal: J Neurosci Date: 1996-06-15 Impact factor: 6.167
Authors: Feng Wei; Chang Shen Qiu; Susan J Kim; Lisa Muglia; James W Maas; Victor V Pineda; Hai Ming Xu; Zhou Feng Chen; Daniel R Storm; Louis J Muglia; Min Zhuo Journal: Neuron Date: 2002-11-14 Impact factor: 17.173