Co-activation of synaptic and extrasynaptic NMDA receptors by neuronal insults determines cell death in acute brain slice |
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| Affiliation: | 1. Department of Neurology, Laboratory of Neurological Diseases, Changzhou No. 2 People’s Hospital, The Affiliated Hospital of Nanjing Medical University, 29 Xinglong Alley, Changzhou, Jiangsu 213003, China;2. Department of Neurology, Foshan First People’s Hospital, The Affiliated Foshan Hospital of Zhongshan University, 81 North Lingnan Avenue, Chancheng District, Foshan, Guangdong 52800, China;3. Department of Physiology and Neuroscience Program, Michigan State University, East Lansing, MI 48824, United States;1. Department of Translational Bioscience, Human Health Therapeutics, National Research Council Canada, 1200 Montreal Road, Ottawa, Ontario, Canada K1A 0R6;2. Université de Nice Sophia Antipolis, IPMC, Sophia Antipolis, F-06560, France;3. CNRS, IPMC, Sophia Antipolis, F-06560, France;1. Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore;2. Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, Singapore;3. Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore;1. Department of Human Anatomy, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China;2. Chinese Medical Association Publishing House, Beijing 100710, PR China;3. Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, PR China;4. Core Facility Center, Capital Medical University, Beijing 100069, PR China;1. Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;2. Laboratory of Membrane Excitability and Disease Mount Sinai School of Medicine, 1425 Madison Avenue, ICAHN 9-26, 28, New York, NY 10029, United States;3. Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, United States;4. Department of Psychiatry, Louisiana State University Health Sciences Center, Shreveport, LA, United States;5. Department of Biomedical Sciences, Marquette University, Milwaukee, WI 53201-1881, United States |
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| Abstract: | Overactivation of NMDA receptors is linked to cell death during neuronal insults. However the precise role of synaptic and extrasynaptic NMDA receptors remains to be further determined. In this study, we used the acute brain slice to examine the contributions of synaptic and extrasynaptic NMDA receptors to neuronal death. By activation of synaptic NMDA receptors with bath application of 100 μM bicuculline in acute brain slices, we observed a significant up-regulation in activation of neuronal survival-related signaling (p-CREB, p-ERK1/2 and p-AKT), without an obvious increase of LDH release and neuronal death. Interestingly, activation of extrasynaptic NMDA receptors alone by high dose of glutamate (200 μM) following blockade of synaptic NMDA receptors with co-application of 20 μM MK801 and 100 μM bicuculline, we failed to observe inhibition of neuronal survival signaling and neuronal damage. In contrast, co-activation of synaptic and extrasynaptic NMDA receptors by applying 200 μM glutamate or oxygen–glucose deprivation (OGD) to acute brain slices for 30 min, we observed a significant inhibition of CREB, ERK1/2 and AKT activation, an increase of LDH release and neuronal condensation. Together, co-activation of synaptic and extrasynaptic NMDA receptors by neuronal insults contributes to cell death in acute brain slice. |
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| Keywords: | Glutamate Synaptic NMDA receptors Extrasynaptic NMDA receptors Excitotoxicity Brain slice |
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