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

Alida Spalloni, Raffaella Geracitano, Nicola Berretta, Carmelo Sgobio, Giorgio Bernardi, Nicola B. Mercuri, Patrizia Longone, Martine Ammassari-Teule

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)505-514
Number of pages10
JournalExperimental Neurology
Volume197
Issue number2
DOIs
Publication statusPublished - Feb 2006

Keywords

  • ALS
  • AMPAR GluR1 subunit
  • Cu/Zn superoxide dismutase (SOD1) gene
  • G93A+/+ mice
  • Glutamate
  • Hippocampus
  • Long-term potentiation
  • Spatial novelty

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

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