Molecular and synaptic changes in the hippocampus underlying superior spatial abilities in pre-symptomatic G93A+/+ mice overexpressing the human Cu/Zn superoxide dismutase (Gly93 --> ALA) mutation.
Although amyotrophic lateral sclerosis (ALS) is mainly considered as a motor disease, extramotor neural and cognitive alterations have also been reported in ALS patients. There is evidence that mutations in the Cu/Zn superoxide dismutase (SOD1) gene are implicated in about 20% of familiar ALS and transgenic mice overexpressing the human Cu/Zn superoxide dismutase (GLY(93) --> ALA) mutation show an ALS-like phenotype. However, while motor behavior has been extensively analyzed in these mutants, little is known on their cognitive abilities. To characterize the pre-symptomatic cognitive profile of G93A+/+ mice, we estimated their capability to detect spatial novelty and examined several indexes of their hippocampal function. We found an enhancement of spatial abilities in mutant mice associated with (1) a higher expression of hippocampal AMPA subunit GluR1 mRNA and of GluR1 protein levels, and (2) an increased induction and maintenance of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Thus, before leading to extensive neuronal excitotoxicity, the high endogenous levels of glutamate present in the brain of pre-symptomatic G93A+/+ mice could mediate site-specific molecular and synaptic changes providing favorable conditions to spatial information processing. These findings suggest that identification of pre-symptomatic behavioral changes in murine models of ALS may point to early neural abnormalities selectively associated with mutations in the Cu/Zn superoxide dismutase (SOD1) gene.
Spalloni
Alida
A
Department of Experimental Neurology, IRCCS S. Lucia Foundation, Via del Fosso di Fiorano 64-65, 00143 Rome, Italy.
Geracitano
Raffaella
R
Berretta
Nicola
N
Sgobio
Carmelo
C
Bernardi
Giorgio
G
Mercuri
Nicola B
NB
Longone
Patrizia
P
Ammassari-Teule
Martine
M
D000409:Alanine / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005106:Exploratory Behavior / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D005998:Glycine / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D017774:Long-Term Potentiation / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D009154:Mutation; D011930:Reaction Time / Q000235:genetics; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013037:Spatial Behavior / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013569:Synapses / Q000502:physiology* / Q000528:radiation effects
D000409:Alanine; D005998:Glycine; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; C104722:glutamate receptor ionotropic, AMPA 2