Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 27, Pages E2518-E2527Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1306832110
Keywords
alpha 7-nicotinics; astrocytes; glutamate receptors
Categories
Funding
- National Institutes of Health [P01 AG010436, P50 AG005131, P01 DA017259, R01 AA020404, R01 NS050636, P01 HD29587, P01 ES016738]
- Department of Defense [W81XWH-10-1-0093]
- National Institute of Neurological Disorders and Stroke Institutional Core Grant [P30 NS076411]
- American Heart Association fellowships
- Ministry of Education and Science of Spain
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Synaptic loss is the cardinal feature linking neuropathology to cognitive decline in Alzheimer's disease (AD). However, the mechanism of synaptic damage remains incompletely understood. Here, using FRET-based glutamate sensor imaging, we show that amyloid-beta peptide (A beta) engages alpha 7 nicotinic acetylcholine receptors to induce release of astrocytic glutamate, which in turn activates extrasynaptic NMDA receptors (eNMDARs) on neurons. In hippocampal autapses, this eNMDAR activity is followed by reduction in evoked and miniature excitatory postsynaptic currents (mEPSCs). Decreased mEPSC frequency may reflect early synaptic injury because of concurrent eNMDAR-mediated NO production, tau phosphorylation, and caspase-3 activation, each of which is implicated in spine loss. In hippocampal slices, oligomeric A beta induces eNMDAR-mediated synaptic depression. In AD-transgenic mice compared with wild type, whole-cell recordings revealed excessive tonic eNMDAR activity accompanied by eNMDAR-sensitive loss of mEPSCs. Importantly, the improved NMDAR antagonist NitroMemantine, which selectively inhibits extrasynaptic over physiological synaptic NMDAR activity, protects synapses from A beta-induced damage both in vitro and in vivo.
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