Enhanced Function and Overexpression of Metabotropic Glutamate Receptors 1 and 5 in the Spinal Cord of the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis during Disease Progression

Glutamate (Glu)-mediated excitotoxicity is a major cause of amyotrophic lateral sclerosis (ALS) and our previous work highlighted that abnormal Glu release may represent a leading mechanism for excessive synaptic Glu. We demonstrated that group I metabotropic Glu receptors (mGluR1, mGluR5) produced abnormal Glu release in SOD1(G93A) mouse spinal cord at a late disease stage (120 days). Here, we studied this phenomenon in pre-symptomatic (30 and 60 days) and early-symptomatic (90 days) SOD1(G93A) mice. The mGluR1/5 agonist (S)-3,5-Dihydroxyphenylglycine (3,5-DHPG) concentration dependently stimulated the release of [(3)H]d-Aspartate ([(3)H]d-Asp), which was comparable in 30- and 60-day-old wild type mice and SOD1(G93A) mice. At variance, [(3)H]d-Asp release was significantly augmented in 90-day-old SOD1(G93A) mice and both mGluR1 and mGluR5 were involved. The 3,5-DHPG-induced [(3)H]d-Asp release was exocytotic, being of vesicular origin and mediated by intra-terminal Ca(2+) release. mGluR1 and mGluR5 expression was increased in Glu spinal cord axon terminals of 90-day-old SOD1(G93A) mice, but not in the whole axon terminal population. Interestingly, mGluR1 and mGluR5 were significantly augmented in total spinal cord tissue already at 60 days. Thus, function and expression of group I mGluRs are enhanced in the early-symptomatic SOD1(G93A) mouse spinal cord, possibly participating in excessive Glu transmission and supporting their implication in ALS. Please define all abbreviations the first time they appear in the abstract, the main text, and the first figure or table caption.