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NMDA receptors activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network.

ABSTRACT: Even before integrating into existing circuitry, adult-born neurons express receptors for neurotransmitters, but the intercellular mechanisms and their impact on neurogenesis remain largely unexplored. Here, we show that neuroblasts born in the postnatal subventricular zone (SVZ) acquire NMDA receptors (NMDARs) during their migration to the olfactory bulb. Along their route, neuroblasts are ensheathed by astrocyte-like cells expressing vesicular glutamate release machinery. Increasing calcium in these specialized astrocytes induced NMDAR activity in neuroblasts, and blocking astrocytic vesicular release eliminated spontaneous NMDAR activity. Single-cell knockout of NMDARs using neonatal electroporation resulted in neuroblast apoptosis at the time of NMDAR acquisition. This cumulated in a 40% loss of neuroblasts along their migratory route, demonstrating that NMDAR acquisition is critical for neuroblast survival prior to entering a synaptic network. In addition, our findings suggest an unexpected mechanism wherein SVZ astrocytes use glutamate signaling through NMDARs to control the number of adult-born neurons reaching their final destination.

SUBMITTER: Platel JC

PROVIDER: S-EPMC2861893 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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NMDA receptors activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network.

Platel Jean-Claude JC Dave Kathleen A KA Gordon Valerie V Lacar Benjamin B Rubio Maria E ME Bordey Angélique A

Neuron 20100301 6

Even before integrating into existing circuitry, adult-born neurons express receptors for neurotransmitters, but the intercellular mechanisms and their impact on neurogenesis remain largely unexplored. Here, we show that neuroblasts born in the postnatal subventricular zone (SVZ) acquire NMDA receptors (NMDARs) during their migration to the olfactory bulb. Along their route, neuroblasts are ensheathed by astrocyte-like cells expressing vesicular glutamate release machinery. Increasing calcium in ...[more]

PMID: 20346761

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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.

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NMDA receptors activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network.

Publications

NMDA receptors activated by subventricular zone astrocytic glutamate are critical for neuroblast survival prior to entering a synaptic network.

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