Abnormal Glu release occurs in the spinal cord of SOD1G93A mice, a transgenic animal model for human ALS. Here we studied the mechanisms underlying Glu release in spinal cord nerve terminals of SOD1G93A mice at a pre-symptomatic disease stage (30 days) and found that the basal release of Glu was more elevated in SOD1G93A with respect to SOD1 mice, and that the surplus of release relies on synaptic vesicle exocytosis. Exposure to high KCl or ionomycin provoked Ca2+-dependent Glu release that was likewise augmented in SOD1G93A mice. Equally, the Ca2+-independent hypertonic sucrose-induced Glu release was abnormally elevated in SOD1G93A mice. Also in this case, the surplus of Glu release was exocytotic in nature. We could determine elevated cytosolic Ca2+ levels, increased phosphorylation of Synapsin-I, which was causally related to the abnormal Glu release measured in spinal cord synaptosomes of pre-symptomatic SOD1G93A mice, and increased phosphorylation of glycogen synthase kinase-3 at the inhibitory sites, an event that favours SNARE protein assembly. Western blot experiments revealed an increased number of SNARE protein complexes at the nerve terminal membrane, with no changes of the three SNARE proteins and increased expression of synaptotagmin-1 and β-Actin, but not of an array of other release-related presynaptic proteins. These results indicate that the abnormal exocytotic Glu release in spinal cord of pre-symptomatic SOD1G93A mice is mainly based on the increased size of the readily releasable pool of vesicles and release facilitation, supported by plastic changes of specific presynaptic mechanisms.
Altered mechanisms underlying the abnormal glutamate release in amyotrophic lateral sclerosis at a pre-symptomatic stage of the disease / T. Bonifacino, L. Musazzi, M. Milanese, M. Seguini, A. Marte, E. Gallia, L. Cattaneo, F. Onofri, M. Popoli, G. Bonanno. - In: NEUROBIOLOGY OF DISEASE. - ISSN 0969-9961. - 95(2016), pp. 122-133.
|Titolo:||Altered mechanisms underlying the abnormal glutamate release in amyotrophic lateral sclerosis at a pre-symptomatic stage of the disease|
MUSAZZI, LAURA (Secondo)
POPOLI, MAURIZIO (Penultimo)
|Parole Chiave:||amyotrophic lateral sclerosis; excessive glutamate release; glutamate excitotoxicity; glutamate release mechanisms; glycogen synthase kinase 3; pre-symptomatic SOD1G93A mice; presynaptic proteins; synapsin-i; neurology|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2016|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.nbd.2016.07.011|
|Appare nelle tipologie:||01 - Articolo su periodico|