Neuroprotective function for ramified microglia in hippocampal excitotoxicity
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RESEARCH
JOURNAL OF NEUROINFLAMMATION
Open Access
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 Biber1,4*
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
Background Brain tissue is highly sensitive to injury because of its restricted regenerative capacity. From the outside, the brain is protected by the skull and the blood-brain barrier [1]. Within the central nervous system (CNS), microglia are the first line of defense that respond rapidly to any type of brain injury [2-5]. This microglia response has long been defined as microglia activation and based on morphological findings, microglia activation was originally described as a stereotypic and graded process [2,5]. This view of microglia function has been challenged in the last years [4]. Various studies using two-photon microscopy have shown that ramified * Correspondence: [email protected] † Contributed equally 1 Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen (UMCG), Rijksuniversiteit Groningen (RUG), Groningen, The Netherlands Full list of author information is available at the end of the article
microglia are not “resting”, as it has long been thought, but instead are very motile cells that constantly move their processes [6-8]. Microglia constantly screen their
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