Apart from the extensive loss of motoneurons, degeneration of midbrain dopaminergic cells have been described in both familiar 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 dopaminegic dysfunction, we have investigated the corticostriatal plasticity in mice overexpressing the human SOD1 (SOD+) and the mutated (Gly93 -> Ala) form (G93A+)of the same enzyme. We show that repetitive stimulation of the corticostriatal pathway generated long- term depression (LTD) in SOD1 mice and in control (G93A-/SOD1 animals) whereas in G93A+ mice, the same stimulation elicited 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 o G93A+ mice causes substantial modifications in striatal plasticity and related behaviors, and may be a cellular substrate of the extrapyramidal motor and cognitive disorders observed in familial and sporadic ALS.
Altered long termcorticostriatal synaptic plasticity in transgenic mice overexpressing human CuZn superoxide dismutase (GLY93 -> Ala) mutation
2003
Abstract
Apart from the extensive loss of motoneurons, degeneration of midbrain dopaminergic cells have been described in both familiar 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 dopaminegic dysfunction, we have investigated the corticostriatal plasticity in mice overexpressing the human SOD1 (SOD+) and the mutated (Gly93 -> Ala) form (G93A+)of the same enzyme. We show that repetitive stimulation of the corticostriatal pathway generated long- term depression (LTD) in SOD1 mice and in control (G93A-/SOD1 animals) whereas in G93A+ mice, the same stimulation elicited 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 o G93A+ mice causes substantial modifications in striatal plasticity and related behaviors, and may be a cellular substrate of the extrapyramidal motor and cognitive disorders observed in familial and sporadic ALS.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
