TY - JOUR
T1 - Plastic and behavioral abnormalities in experimental Huntington's disease
T2 - A crucial role for cholinergic interneurons
AU - Picconi, Barbara
AU - Passino, Enrica
AU - Sgobio, Carmelo
AU - Bonsi, Paola
AU - Barone, Ilaria
AU - Ghiglieri, Veronica
AU - Pisani, Antonio
AU - Bernardi, Giorgio
AU - Ammassari-Teule, Martine
AU - Calabresi, Paolo
PY - 2006/4
Y1 - 2006/4
N2 - 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.
AB - 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.
KW - 3-Nitropropionic acid
KW - HD animal models
KW - Huntington's disease
KW - Plastic abnormalities
KW - R6/2 mice
KW - Striatum
KW - Synaptic plasticity
UR - http://www.scopus.com/inward/record.url?scp=33645081706&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33645081706&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2005.10.009
DO - 10.1016/j.nbd.2005.10.009
M3 - Article
C2 - 16326108
AN - SCOPUS:33645081706
VL - 22
SP - 143
EP - 152
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 1
ER -