title: Plastic and behavioral abnormalities in experimental Huntington's disease: a crucial role for cholinergic interneurons.
abstract: Huntington's disease (HD) is a fatal hereditary neurodegenerative disease causing degeneration of striatal spiny neurons, whereas cholinergic interneurons are spared. This cell-type specific pathology produces an array of abnormalities including involuntary movements, cognitive impairments, and psychiatric disorders. Although the genetic mutation responsible for HD has been identified, little is known about the early synaptic changes occurring within the striatal circuitry at the onset of clinical symptoms. We therefore studied the synaptic plasticity of spiny neurons and cholinergic interneurons in two animal models of early HD. As a pathogenetic model, we used the chronic subcutaneous infusion of the mitochondrial toxin 3-nitropropionic acid (3-NP) in rats. This treatment caused striatal damage and impaired response flexibility in the cross-maze task as well as defective extinction of conditioned fear suggesting a perseverative behavior. In these animals, we observed a loss of depotentiation in striatal spiny neurons and a lack of long-term potentiation (LTP) in cholinergic interneurons. These abnormalities of striatal synaptic plasticity were also observed in R6/2 transgenic mice, a genetic model of HD, indicating that both genetic and phenotypic models of HD show cell-type specific alterations of LTP. We also found that in control rats, as well as in wild-type (WT) mice, depotentiation of spiny neurons was blocked by either scopolamine or hemicholinium, indicating that reversal of LTP requires activation of muscarinic receptors by endogenous acetylcholine. Our findings suggest that the defective plasticity of cholinergic interneurons could be the primary event mediating abnormal functioning of striatal circuits, and the loss of behavioral flexibility typical of early HD might largely depend on cell-type specific plastic abnormalities.
authors.affiliation: Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, Via del Fosso di Fiorano 65, 00143 Rome, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Picconi
authors.forename: Enrica
authors.initials: E
authors.lastname: Passino
authors.forename: Carmelo
authors.initials: C
authors.lastname: Sgobio
authors.forename: Paola
authors.initials: P
authors.lastname: Bonsi
authors.forename: Ilaria
authors.initials: I
authors.lastname: Barone
authors.forename: Veronica
authors.initials: V
authors.lastname: Ghiglieri
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisani
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Martine
authors.initials: M
authors.lastname: Ammassari-Teule
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002799:Cholinergic Fibers / Q000378:metabolism* / Q000473:pathology; D003292:Convulsants; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology; D017774:Long-Term Potentiation / Q000235:genetics; D008297:Male; D001523:Mental Disorders / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D018727:Muscarinic Antagonists / Q000494:pharmacology; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology*; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D051381:Rats; D011917:Rats, Inbred Lew; D013569:Synapses / Q000378:metabolism / Q000473:pathology
chemical_list: D003292:Convulsants; D018727:Muscarinic Antagonists; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D000109:Acetylcholine; C015392:3-nitropropionic acid