Glutamate-mediated excitotoxicity plays a major role in the degeneration of motor neurons in amyotrophic lateral sclerosis and reduced astrocytary glutamate transport, which in turn increases the synaptic availability of the amino acid neurotransmitter, was suggested as a cause. Alternatively, here we report our studies on the exocytotic release of glutamate as a possible source of excessive glutamate transmission. The basal glutamate efflux from spinal cord nerve terminals of mice-expressing human soluble superoxide dismutase (SOD1) with the G93A mutation [SOD1/G93A(+)], a transgenic model of amyotrophic lateral sclerosis, was elevated when compared with transgenic mice expressing the wild-type human SOD1 or to non-transgenic controls. Exposure to 15 mM KCl or 0.3 μM ionomycin provoked Ca(2+)-dependent glutamate release that was dramatically increased in late symptomatic and in pre-symptomatic SOD1/G93A(+) mice. Increased Ca(2+) levels were detected in SOD1/G93A(+) mouse spinal cord nerve terminals, accompanied by increased activation of Ca(2+)/calmodulin-dependent kinase II and increased phosphorylation of synapsin I. In line with these findings, release experiments suggested that the glutamate release augmentation involves the readily releasable pool of vesicles and a greater capability of these vesicles to fuse upon stimulation in SOD1/G93A(+) mice.
Abnormal exocytotic release of glutamate in a mouse model of amyotrophic lateral sclerosis / M. Milanese, S. Zappettini, F. Onofri, L. Musazzi, D. Tardito, T. Bonifacino, M. Messa, G. Racagni, C. Usai, F. Benfenati, M. Popoli, G. Bonanno. - In: JOURNAL OF NEUROCHEMISTRY. - ISSN 0022-3042. - 116:6(2011 Mar), pp. 1028-1042.
|Titolo:||Abnormal exocytotic release of glutamate in a mouse model of amyotrophic lateral sclerosis|
|Parole Chiave:||amyotrophic lateral sclerosis; exocytosis; glutamate release; SOD1/G93A expressing mice; synapsin I|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||mar-2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1111/j.1471-4159.2010.07155.x|
|Appare nelle tipologie:||01 - Articolo su periodico|