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Neuroprotective function for ramified microglia in hippocampal excitotoxicity

Jonathan Vinet1, Hilmar RJ van Weering1, Annette Heinrich4, Roland E Kälin2, Anja Wegner2, Nieske Brouwer1, Frank L Heppner2, Nico van Rooijen3, Hendrikus WGM Boddeke1 and Knut Biber14*

Author Affiliations

1 Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen (UMCG), Rijksuniversiteit Groningen (RUG), Groningen, The Netherlands

2 Department of Neuropathology, Charité-Universitätsmedizin Berlin, Berlin, Germany

3 Department of Molecular Cell biology, Free University Medical Center (VUMC), Amsterdam, The Netherlands

4 Department of Psychiatry and Psychotherapy, Section of Molecular Psychiatry, University of Freiburg, Freiburg, Germany

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Journal of Neuroinflammation 2012, 9:27  doi:10.1186/1742-2094-9-27

Published: 31 January 2012

Abstract

Background

Most of the known functions of microglia, including neurotoxic and neuroprotective properties, are attributed to morphologically-activated microglia. Resting, ramified microglia are suggested to primarily monitor their environment including synapses. Here, we show an active protective role of ramified microglia in excitotoxicity-induced neurodegeneration.

Methods

Mouse organotypic hippocampal slice cultures were treated with N-methyl-D-aspartic acid (NMDA) to induce excitotoxic neuronal cell death. This procedure was performed in slices containing resting microglia or slices that were chemically or genetically depleted of their endogenous microglia.

Results

Treatment of mouse organotypic hippocampal slice cultures with 10-50 μM N-methyl-D-aspartic acid (NMDA) induced region-specific excitotoxic neuronal cell death with CA1 neurons being most vulnerable, whereas CA3 and DG neurons were affected less. Ablation of ramified microglia severely enhanced NMDA-induced neuronal cell death in the CA3 and DG region rendering them almost as sensitive as CA1 neurons. Replenishment of microglia-free slices with microglia restored the original resistance of CA3 and DG neurons towards NMDA.

Conclusions

Our data strongly suggest that ramified microglia not only screen their microenvironment but additionally protect hippocampal neurons under pathological conditions. Morphological activation of ramified microglia is thus not required to influence neuronal survival.

Keywords:
Microglia; NMDA; Excitotoxicity; Organotypic hippocampal slice cultures; Clodronate; Ganciclovir