期刊
CELL REPORTS
卷 12, 期 8, 页码 1353-1366出版社
CELL PRESS
DOI: 10.1016/j.celrep.2015.07.038
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资金
- Alexander von Humboldt Foundation
- ERC Advanced Grant
- DFG Graduate College 791 [SFB636]
- Graduate Academy (Excellence Initiative) of Heidelberg University
The health of neurons is critically dependent on the relative signaling intensities of survival-promoting synaptic and death-inducing extrasynaptic NMDA receptors. Here, we show that BDNF is a regulator of this balance and promotes neuroprotection by reducing toxic NMDA receptor signaling. BDNF acts by initiating synaptic NMDA-receptor/nuclear-calcium- driven adaptogenomics, leading to increased expression of inhibin beta-A (inhba). Inhibin beta-A (its homodimer is known as activin A) in turn reduces neurotoxic extrasynaptic NMDA-receptor-mediated calcium influx, thereby shielding neurons against mitochondrial dysfunction, a major cause of excitotoxicity. Thus, BDNF induces acquired neuroprotection by enhancing synaptic activity and lowering extrasynaptic NMDA receptor death signaling through a nuclear calcium-inhibin beta-A pathway. This process, which confers protection against ischemic brain damage in a mouse stroke model, may be compromised in Huntington's disease, Alzheimer's disease, or aging-related neurodegenerative conditions that are associated with reduced BDNF levels and/or enhanced extrasynaptic NMDA receptor signaling.
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