TY - JOUR
T1 - 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
AU - Spalloni, Alida
AU - Geracitano, Raffaella
AU - Berretta, Nicola
AU - Sgobio, Carmelo
AU - Bernardi, Giorgio
AU - Mercuri, Nicola B.
AU - Longone, Patrizia
AU - Ammassari-Teule, Martine
PY - 2006/2
Y1 - 2006/2
N2 - 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.
AB - 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.
KW - ALS
KW - AMPAR GluR1 subunit
KW - Cu/Zn superoxide dismutase (SOD1) gene
KW - G93A+/+ mice
KW - Glutamate
KW - Hippocampus
KW - Long-term potentiation
KW - Spatial novelty
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U2 - 10.1016/j.expneurol.2005.10.014
DO - 10.1016/j.expneurol.2005.10.014
M3 - Article
C2 - 16309674
AN - SCOPUS:30544454222
VL - 197
SP - 505
EP - 514
JO - Experimental Neurology
JF - Experimental Neurology
SN - 0014-4886
IS - 2
ER -