The causes of amyotrophic lateral sclerosis (ALS) are mostly undefined; however, excitotoxic injury and astrogliosis may contribute to motor neuron (MN) degeneration. Group I metabotropic glutamate (mGlu) receptors are over-expressed in reactive astrocytes in ALS, but the functional significance of this over-expression is presently unknown. We examined the role of group I mGlu receptors on excitotoxic death of spinal cord MNs grown in cultures enriched of astrocytes bearing a reactive phenotype. A prolonged exposure to the selective non-competitive mGlu5 receptor antagonist MPEP reduced AMPA-mediated toxicity and cobalt uptake in MNs. Expression levels of the GluR1 (but not GluR2) AMPA receptor subunit and levels of brain-derived neurotrophic factor (BDNF) were reduced in mixed spinal cord cultures pretreated with MPEP. In addition, neuroprotection by MPEP was less than additive with that produced by a neutralizing anti-BDNF antibody and a treatment with exogenous BDNF masked the protective effect of MPEP, suggesting that mGlu5 receptors and BDNF converge in facilitating excitotoxic MN death. The protective effect of MPEP was absent in cultures with a reduced number of astrocytes. We suggest that blocking astrocytic mGlu5 receptors is a potential therapeutic strategy in ALS.
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