Glutamate (Glu) excitotoxicity plays a major role in amyotrophic lateral sclerosis (ALS) and elevated extracellular Glu levels were found in patients and animal models of the disease. Reduced astrocyte uptake was suggested as the main cause for increased Glu availability. On the basis of our experiments, we postulated that abnormal neurotransmitter release represents another source for elevated Glu. Indeed, we found that neuronal Glu release from spinal cord synaptosomes is abnormally high in the spinal cord of pre-symptomatic and symptomatic SOD1G93A mice, a widely used experimental model of ALS, under resting conditions and upon exposure to different stimuli able to induce Glu exocytosis, including KCl depolarization, ionomycin, hypertonic sucrose or activation of Group I metabotropic Glu receptors. Also GABA and glycine induced Glu release in mouse spinal cord synaptosomes by activation of the respective transportes expressed at Glu-releasing terminals (heterotransporters) and also this effect was more elevated in SOD1G93A mice than in controls. We report here the effect of GABA on Glu release from gliosomes, an astrocytic preparation obtained by tissue homogenization and Percoll® gradient purification, that represent viable particles originating from the astrocytes sorrounding the synapses. Interestingly, GABA induced Glu release by a heterotransporter-mediated mechanism also from gliosomes purified from the spinal cord of SOD1G93A mice and the effect of GABA was up regulated, leading to over release of Glu. The excessive release of Glu evoked by GABA was already present in the pre-symptomatic stage of the disease. Our results indicate that abnormal Glu release from astrocytes is present in pre-symptomatic and symptomatic SOD1G93A mice. Thus, astrocytes may contribute to the increased concentration of Glu at glutamatergic synapses, to the activation of presynaptic and post-synaptic Glu receptors, and to excitotoxicity.
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|Titolo:||Astrocyte contribution to the excessive glutamate release in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis|
|Data di pubblicazione:||2016|
|Appare nelle tipologie:||04.01 - Contributo in atti di convegno|