Altered long-term corticostriatal synaptic plasticity in transgenic mice overexpressing human Cu/Zn superoxide dismutase (Gly93→Ala) mutation

R. Geracitano, E. Paolucci, S. Prisco, E. Guatteo, C. Zona, P. Longone, M. Ammassari-Teule, G. Bernardi, N. Berretta, N. B. Mercuri

Research output: Contribution to journalArticle

Abstract

Apart from the extensive loss of motor neurons, degeneration of midbrain dopaminergic cells has been described in both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Mice overexpressing the mutant human Cu/Zn superoxide dismutase (SOD1) show an ALS-like phenotype in that they show a progressive death of motor neurons accompanied by degeneration of dopaminergic cells. To describe the functional alterations specifically associated with this dopaminergic dysfunction, we have investigated the corticostriatal synaptic plasticity in mice overexpressing the human SOD1 (SOD1+) and the mutated (Gly93→Ala) form (G93A+) of the same enzyme. We show that repetitive stimulation of the corticostriatal pathway generates long-term depression (LTD) in SOD1+ mice and in control (G93A-/SOD1-) animals, whereas in G93A+ mice the same stimulation generates an N-methyl-D-aspartic acid receptor-dependent long-term potentiation. No significant alterations were found in the intrinsic membrane properties of striatal medium spiny neurons and basal corticostriatal synaptic transmission of G93A+ mice. Bath perfusion of dopamine or the D2 dopamine receptor agonist quinpirole restored LTD in G93A+ mice. Consistent with these in vitro results, habituation of locomotor activity and striatal-dependent active avoidance learning were impaired in G93A+ mice. Thus, degeneration of dopaminergic neurons in the substantia nigra of G93A+ mice causes substantial modifications in striatal synaptic plasticity and related behaviors, and may be a cellular substrate of the extrapyramidal motor and cognitive disorders observed in familial and sporadic ALS.

Original languageEnglish
Pages (from-to)399-408
Number of pages10
JournalNeuroscience
Volume118
Issue number2
DOIs
Publication statusPublished - May 8 2003

Fingerprint

Neuronal Plasticity
Transgenic Mice
Mutation
Corpus Striatum
Nerve Degeneration
Motor Neurons
Depression
Avoidance Learning
Quinpirole
Problem-Based Learning
Superoxide Dismutase-1
Long-Term Potentiation
Dopaminergic Neurons
Dopamine Agonists
Amyotrophic Lateral Sclerosis
Substantia Nigra
N-Methylaspartate
Locomotion
Mesencephalon
Baths

Keywords

  • Amyotrophic lateral sclerosis
  • LTD
  • LTP
  • SOD1
  • Striatum

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Altered long-term corticostriatal synaptic plasticity in transgenic mice overexpressing human Cu/Zn superoxide dismutase (Gly93→Ala) mutation. / Geracitano, R.; Paolucci, E.; Prisco, S.; Guatteo, E.; Zona, C.; Longone, P.; Ammassari-Teule, M.; Bernardi, G.; Berretta, N.; Mercuri, N. B.

In: Neuroscience, Vol. 118, No. 2, 08.05.2003, p. 399-408.

Research output: Contribution to journalArticle

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