Group i metabotropic glutamate autoreceptors induce abnormal glutamate exocytosis in a mouse model of amyotrophic lateral sclerosis

Francesco Giribaldi, Marco Milanese, Tiziana Bonifacino, Pia Irene Anna Rossi, Silvia Di Prisco, Anna Pittaluga, Carlo Tacchetti, Aldamaria Puliti, Cesare Usai, Giambattista Bonanno

Research output: Contribution to journalArticlepeer-review

Abstract

Glutamate-mediated excitotoxicity plays a major role in ALS and reduced astrocytic glutamate transport was suggested as a cause. Based on previous work we have proposed that abnormal release may represent another source of excessive glutamate. In this line, here we studied the modulation of glutamate release in ALS by Group I metabotropic glutamate (mGlu) receptors, that comprise mGlu1 and mGlu5 members. Synaptosomes from the lumbar spinal cord of SOD1/G93A mice, a widely used murine model for human ALS, and controls were used in release, confocal or electron microscopy and Western blot experiments. Concentrations of the mGlu1/5 receptor agonist 3,5-DHPG >0.3 μM stimulated the release of [3H]d- aspartate, used to label the releasing pools of glutamate, both in control and SOD1/G93A mice. At variance, ≤0.3 μM 3,5-DHPG increased [3H]d-Aspartate release in SOD1/G93A mice only. Experiments with selective antagonists indicated the involvement of both mGlu1 and mGlu5 receptors, mGlu5 being preferentially involved in the high potency effects of 3,5-DHPG. High 3,5-DHPG concentrations increased IP3 formation in both mouse strains, whereas low 3,5-DHPG did it in SOD1/G93A mice only. Release experiments confirmed that 3,5-DHPG elicited [3H]d-Aspartate exocytosis involving intra-terminal Ca2+ release through IP3-sensitive channels. Confocal microscopy indicated the co-existence of both receptors presynaptically in the same glutamatergic nerve terminal in SOD1/G93A mice. To conclude, activation of mGlu1/5 receptors produced abnormal glutamate release in SOD1/G93A mice, suggesting that these receptors are implicated in ALS and that selective antagonists may be predicted for new therapeutic approaches. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Original languageEnglish
Pages (from-to)253-263
Number of pages11
JournalNeuropharmacology
Volume66
DOIs
Publication statusPublished - Mar 2013

Keywords

  • Amyotrophic lateral sclerosis
  • Glutamate release
  • Neurotoxicity
  • Pre-synaptic mGlu1 receptors
  • Pre-synaptic mGlu5 receptors
  • SOD1/G93A mice

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

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