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A? induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

ABSTRACT: 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-? peptide (A?) engages ?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? 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?-induced damage both in vitro and in vivo.

SUBMITTER: Talantova M

PROVIDER: S-EPMC3704025 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

Talantova Maria M Sanz-Blasco Sara S Zhang Xiaofei X Xia Peng P Akhtar Mohd Waseem MW Okamoto Shu-ichi S Dziewczapolski Gustavo G Nakamura Tomohiro T Cao Gang G Pratt Alexander E AE Kang Yeon-Joo YJ Tu Shichun S Molokanova Elena E McKercher Scott R SR Hires Samuel Andrew SA Sason Hagit H Stouffer David G DG Buczynski Matthew W MW Solomon James P JP Michael Sarah S Powers Evan T ET Kelly Jeffery W JW Roberts Amanda A Tong Gary G Fang-Newmeyer Traci T Parker James J Holland Emily A EA Zhang Dongxian D Nakanishi Nobuki N Chen H-S Vincent HS Wolosker Herman H Wang Yuqiang Y Parsons Loren H LH Ambasudhan Rajesh R Masliah Eliezer E Heinemann Stephen F SF Piña-Crespo Juan C JC Lipton Stuart A SA

Proceedings of the National Academy of Sciences of the United States of America 20130617 27

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-β peptide (Aβ) engages α7 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 reduc ...[more]

PMID: 23776240

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Project description:BackgroundNeutrophil depletion improves neurologic outcomes in experimental sepsis/brain injury. We hypothesized that neutrophils may exacerbate neuronal injury through the release of neurotoxic quantities of the neurotransmitter glutamate.MethodsReal-time glutamate release by primary human neutrophils was determined using enzymatic biosensors. Bacterial and direct protein-kinase C (Phorbol 12-myristate 13-acetate; PMA) activation of neutrophils in human whole blood, isolated neutrophils or human cell lines were compared in the presence/absence of N-Methyl-d-aspartic acid receptor (NMDAR) antagonists. Bacterial and direct activation of neutrophils from wild-type and transgenic murine neutrophils deficient in NMDAR-scaffolding proteins were compared using flow cytometry (phagocytosis, reactive oxygen species (ROS) generation) and real-time respirometry (oxygen consumption).FindingsBoth glutamate and the NMDAR co-agonist d-serine are rapidly released by neutrophils in response to bacterial and PMA-induced activation. Pharmacological NMDAR blockade reduced both the autocrine release of glutamate, d-serine and the respiratory burst by activated primary human neutrophils. A highly specific small-molecule inhibitor ZL006 that limits NMDAR-mediated neuronal injury also reduced ROS by activated neutrophils in a murine model of peritonitis, via uncoupling of the NMDAR GluN2B subunit from its' scaffolding protein, postsynaptic density protein-95 (PSD-95). Genetic ablation of PSD-95 reduced ROS production by activated murine neutrophils. Pharmacological blockade of the NMDAR GluN2B subunit reduced primary human neutrophil activation induced by Pseudomonas fluorescens, a glutamate-secreting Gram-negative bacillus closely related to pathogens that cause hospital-acquired infections.InterpretationThese data suggest that release of glutamate by activated neutrophils augments ROS production in an autocrine manner via actions on NMDAR expressed by these cells. FUND: GLA: Academy Medical Sciences/Health Foundation Clinician Scientist. AVG is a Wellcome Trust Senior Research Fellow.

Dataset Information

A? induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

Publications

Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss.

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