Delayed inhibition of tonic inhibition enhances functional recovery following experimental ischemic stroke
Autor: | Krista M. Rodgers, Christian Schroeder, Himmat Grewal, James E. Orfila, Frank Strnad, Takeru Shimizu, Paco S. Herson, Andra Dingman, Timothy J. Bernard, Nidia Quillinan, Myriam Moreno, Robert M. Dietz, Richard J. Traystman, Joan C Yonchek, Wendy B. Macklin |
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Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Male Time Factors Tonic inhibition Long-Term Potentiation Hippocampus Brain Ischemia 03 medical and health sciences Mice 0302 clinical medicine Cognition medicine Animals Stroke gamma-Aminobutyric Acid Memory Disorders Neuronal Plasticity business.industry Original Articles Recovery of Function medicine.disease Functional recovery Receptors GABA-A Mice Inbred C57BL 030104 developmental biology Neurology Synaptic plasticity Ischemic stroke Neurology (clinical) Cardiology and Cardiovascular Medicine business Neuroscience 030217 neurology & neurosurgery |
Zdroj: | J Cereb Blood Flow Metab |
Popis: | The current study focuses on the ability to improve cognitive function after stroke with interventions administered at delayed/chronic time points. In light of recent studies demonstrating delayed GABA antagonists improve motor function, we utilized electrophysiology, biochemistry and neurobehavioral methods to investigate the role of α5 GABAA receptors on hippocampal plasticity and functional recovery following ischemic stroke. Male C57Bl/6 mice were exposed to 45 min transient middle cerebral artery occlusion and analysis of synaptic and functional deficits performed 7 or 30 days after recovery. Our findings indicate that hippocampal long-term potentiation (LTP) is impaired 7 days after stroke and remain impaired for at least 30 days. We demonstrate that ex vivo administration of L655,708 reversed ischemia-induced plasticity deficits and importantly, in vivo administration at delayed time-points reversed stroke-induced memory deficits. Western blot analysis of hippocampal tissue reveals proteins responsible for GABA synthesis are upregulated (GAD65/67 and MAOB), increasing GABA in hippocampal interneurons 30 days after stroke. Thus, our data indicate that both synaptic plasticity and memory impairments observed after stroke are caused by excessive tonic GABA activity, making inhibition of specific GABA activity at delayed timepoints a potential therapeutic approach to improve functional recovery and reverse cognitive impairments after stroke. |
Databáze: | OpenAIRE |
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