alpha-Amino-3-hydroxy-5-methyl-isoxazole-4-propionate receptors in spinal cord motor neurons are altered in transgenic mice overexpressing human Cu,Zn superoxide dismutase (Gly93-->Ala) mutation.
There are many evidences implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS). This neurodegenerative disorder is characterized by the progressive loss of motor neurons, whose pathogenesis is thought to involve Ca(2+) influx mediated by alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate receptors (AMPARs). In the present study we report alterations in the AMPARs function in a transgenic mouse-model of the human SOD1(G93A) familial ALS. Compared with those expressed in motor neurons carrying the human wild type gene, AMPAR-gated channels expressed in motor neurons carrying the human mutant gene exhibited modified permeability, altered agonist cooperativity between the sites involved in the process of channel opening and were responsible for slower spontaneous synaptic events. These observations demonstrate that the SOD1(G93A) mutation induces changes in AMPAR functions which may underlie the increased vulnerability of motor neurons to glutamatergic excitotoxicity in ALS.
Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier 1, 00133 Roma, Italy.
M
M
Pieri
C
C
Gaetti
A
A
Spalloni
S
S
Cavalcanti
N
N
Mercuri
G
G
Bernardi
P
P
Longone
C
C
Zona
D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D004594:Electrophysiology; D005998:Glycine / Q000235:genetics; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology / Q000378:metabolism*; D009154:Mutation; D018408:Patch-Clamp Techniques; D018091:Receptors, AMPA / Q000378:metabolism*; D013116:Spinal Cord / Q000201:enzymology / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D018091:Receptors, AMPA; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000409:Alanine; D005998:Glycine