title: Long-term inhibition of Rho-kinase restores the LTP impaired in chronic forebrain ischemia rats by regulating GABAA and GABAB receptors.
abstract: We previously demonstrated that inactivation of Rho-kinase by hydroxyfasudil could impact N-methyl-d-aspartate (NMDA) excitatory interneurons in the hippocampus and attenuate the spatial learning and memory dysfunction of rats caused by chronic forebrain hypoperfusion ischemia. Complementary interactions between the excitatory neurotransmitter glutamate and the inhibitory neurotransmitter GABA form the molecular basis of synaptic plasticity and cognitive performance. However, whether the GABAergic inhibitory interneurons are involved in the mechanisms underlying these processes remains unclear. Here, we further examined the role of GABAergic interneurons in the neuroprotective effect of the Rho-kinase inhibitor. Chronic forebrain ischemia was induced in Wistar rats by bilateral common carotid artery occlusion (BCAO). The general synaptic transmission and long-term potentiation (LTP) of hippocampal CA3 neurons were evaluated at 30 days after sham surgery or BCAO. Real-time PCR and Western blot analyses were conducted to determine the effect of the Rho-kinase inhibitor hydroxyfasudil on GABAergic inhibitory interneuron expression and function after ischemia. Hydroxyfasudil showed no significant effect on general synaptic transmission, but it could abolish the inhibition of LTP induced by chronic forebrain ischemia. Moreover, the mRNA and protein levels of GABAA and GABAB in three brain regions after ischemia were markedly decreased, and hydroxyfasudil could up-regulate all mRNA and protein expression levels in these areas except for GABAA mRNA in the cerebral cortex and striatum. Using phosphorylation antibodies against specific sites on the GABAA and GABAB receptors, we further demonstrated that hydroxyfasudil could inhibit GABAergic interneuron phosphorylation triggered by the theta burst stimulation. In summary, our results indicated that the inactivation of Rho-kinase could enhance GABAA and GABAB expressions by different mechanisms to guarantee the induction of hippocampal LTP, and it could decrease the phosphorylation level of GABAergic inhibitory interneurons to promote the LTP induction rate and magnitude, hence improving the cognitive deficit suffered after chronic forebrain ischemia.
authors: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, PR China.
authors: L
authors: L
authors: Huang
authors: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, PR China.
authors: L B
authors: LB
authors: Zhao
authors: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, PR China.
authors: Z Y
authors: ZY
authors: Yu
authors: Central Laboratory, Peking University People's Hospital, Beijing 100044, PR China.
authors: X J
authors: XJ
authors: He
authors: Central Laboratory, Peking University People's Hospital, Beijing 100044, PR China.
authors: L P
authors: LP
authors: Ma
authors: Central Laboratory, Peking University People's Hospital, Beijing 100044, PR China.
authors: N
authors: N
authors: Li
authors: Department of Pharmacology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
authors: L J
authors: LJ
authors: Guo
authors: Department of Pharmacy, Peking University People's Hospital, Beijing 100044, PR China. Electronic address: pkuph_yjk@163.com.
authors: W Y
authors: WY
authors: Feng
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects* / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases
keywords: GABA(A); GABA(B); LTP; Rho-kinase; chronic forebrain ischemia; hydroxyfasudil