Plastic and behavioral abnormalities in experimental Huntington's disease: a crucial role for cholinergic interneurons.
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.
Picconi
Barbara
B
Laboratorio di Neurofisiologia, Fondazione Santa Lucia, IRCCS, Via del Fosso di Fiorano 65, 00143 Rome, Italy.
Passino
Enrica
E
Sgobio
Carmelo
C
Bonsi
Paola
P
Barone
Ilaria
I
Ghiglieri
Veronica
V
Pisani
Antonio
A
Bernardi
Giorgio
G
Ammassari-Teule
Martine
M
Calabresi
Paolo
P
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
D003292:Convulsants; D018727:Muscarinic Antagonists; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D000109:Acetylcholine; C015392:3-nitropropionic acid