title: Altered long-term corticostriatal synaptic plasticity in transgenic mice overexpressing human CU/ZN superoxide dismutase (GLY(93)-->ALA) mutation.
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 (Gly(93)-->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 D(2) 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.
authors.affiliation: Fondazione Santa Lucia IRCCS, Via Ardeatina 306, 00179 Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Geracitano
authors.forename: E
authors.initials: E
authors.lastname: Paolucci
authors.forename: S
authors.initials: S
authors.lastname: Prisco
authors.forename: E
authors.initials: E
authors.lastname: Guatteo
authors.forename: C
authors.initials: C
authors.lastname: Zona
authors.forename: P
authors.initials: P
authors.lastname: Longone
authors.forename: M
authors.initials: M
authors.lastname: Ammassari-Teule
authors.forename: G
authors.initials: G
authors.lastname: Bernardi
authors.forename: N
authors.initials: N
authors.lastname: Berretta
authors.forename: N B
authors.initials: NB
authors.lastname: Mercuri
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000409:Alanine / Q000235:genetics; D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D003342:Corpus Striatum / Q000502:physiology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004558:Electric Stimulation; D005838:Genotype; D005998:Glycine / Q000235:genetics; D006179:Gyrus Cinguli / Q000033:anatomy & histology / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D009434:Neural Pathways; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D019257:Quinpirole / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D018491:Dopamine Agonists; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C056639:2-amino-5-phosphopentanoic acid; D013482:Superoxide Dismutase; D014633:Valine; D000409:Alanine; D002118:Calcium; D005998:Glycine