期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 39, 期 6, 页码 1122-1137出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X18755661
关键词
Astrocyte; cannabinoid 1 receptor; JZL195; long-term depression; stroke
资金
- International Cooperation and Exchange of the National Natural Science Foundation of China [81420108013]
- Canadian Institutes of Health Research [MOP 123256]
- Canadian Foundation for Innovation [19317]
- Shaanxi Province Natural Science Foundation [2016JQ8024]
- NIH [1R01MH099554-01]
- National Natural Science Foundation of China [81771227]
Ischemia not only activates cell death pathways but also triggers endogenous protective mechanisms. However, it is largely unknown what is the essence of the endogenous neuroprotective mechanisms induced by preconditioning. In this study we demonstrated that systemic injection of JZL195, a selective inhibitor of eCB clearance enzymes, induces in vivo long-term depression at CA3-CA1 synapses and at PrL-NAc synapses produces neuroprotection. JZL195-elicited long-term depression is blocked by AM281, the antagonist of cannabinoid 1 receptor (CB1R) and is abolished in mice lacking cannabinoid CB1 receptor (CB1R) in astroglial cells, but is conserved in mice lacking CB1R in glutamatergic or GABAergic neurons. Blocking the glutamate NMDA receptor and the synaptic trafficking of glutamate AMPA receptor abolishes both long-term depression and neuroprotection induced by JZL195. Mice lacking CB1R in astroglia show decreased neuronal death following cerebral ischemia. Thus, an acute elevation of extracellular eCB following eCB clearance inhibition results in neuroprotection through long-term depression induction after sequential activation of astroglial CB1R and postsynaptic glutamate receptors.
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