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Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism

Picconi, B; Gardoni, F; Centonze, D; Mauceri, D; Cenci Nilsson, Angela LU ; Bernardi, G; Calabresi, P and Di Luca, M (2004) In Journal of Neuroscience 24(23). p.5283-5291
Abstract
The NMDA receptor complex represents a key molecular element in the pathogenesis of long-term synaptic changes and motor abnormalities in Parkinson's disease (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)-denervated striata. These effects are accompanied by an increase in striatal levels of alphaCa(2+)-calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, along with a higher recruitment of activated alphaCaMKII to the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride, but not with... (More)
The NMDA receptor complex represents a key molecular element in the pathogenesis of long-term synaptic changes and motor abnormalities in Parkinson's disease (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)-denervated striata. These effects are accompanied by an increase in striatal levels of alphaCa(2+)-calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, along with a higher recruitment of activated alphaCaMKII to the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride, but not with L-sulpiride, mimicked the effect of DA denervation on both alphaCaMKII autophosphorylation and corticostriatal synaptic plasticity. In addition to normalizing alphaCaMKII autophosphorylation levels as well as assembly and anchoring of the kinase to the NMDA receptor complex, intrastriatal administration of the CaMKII inhibitors KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl] methylamino] methyl] phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide) and antennapedia autocamtide-related inhibitory peptide II is able to reverse both the alterations in corticostriatal synaptic plasticity and the deficits in spontaneous motor behavior that are found in an animal model of PD. The same beneficial effects are produced by a regimen of L-3,4-dihydroxyphenylalanine(L-DOPA) treatment, which is able to normalize alphaCaMKII autophosphorylation. These data indicate that abnormal alphaCaMKII autophosphorylation plays a causal role in the alterations of striatal plasticity and motor behavior that follow DA denervation. Normalization of CaMKII activity may be an important underlying mechanism of the therapeutic action of L-DOPA in PD. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
rat, LTP, CaMKII, 6-OHDA, Parkinson's disease, striatum
in
Journal of Neuroscience
volume
24
issue
23
pages
5283 - 5291
publisher
Society for Neuroscience
external identifiers
  • pmid:15190099
  • wos:000221924800001
  • scopus:2942586826
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.1224-04.2004
language
English
LU publication?
yes
id
dd19855c-025e-4a5e-9215-43f4f9e9a4a1 (old id 275240)
date added to LUP
2007-10-29 16:03:40
date last changed
2017-10-01 04:51:24
@article{dd19855c-025e-4a5e-9215-43f4f9e9a4a1,
  abstract     = {The NMDA receptor complex represents a key molecular element in the pathogenesis of long-term synaptic changes and motor abnormalities in Parkinson's disease (PD). Here we show that NMDA receptor 1 (NR1) subunit and postsynaptic density (PSD)-95 protein levels are selectively reduced in the PSD of dopamine (DA)-denervated striata. These effects are accompanied by an increase in striatal levels of alphaCa(2+)-calmodulin-dependent protein kinase II (alphaCaMKII) autophosphorylation, along with a higher recruitment of activated alphaCaMKII to the regulatory NMDA receptor NR2A-NR2B subunits. Acute treatment of striatal slices with R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaz epine hydrochloride, but not with L-sulpiride, mimicked the effect of DA denervation on both alphaCaMKII autophosphorylation and corticostriatal synaptic plasticity. In addition to normalizing alphaCaMKII autophosphorylation levels as well as assembly and anchoring of the kinase to the NMDA receptor complex, intrastriatal administration of the CaMKII inhibitors KN-93 (N-[2-[[[3-(4-chlorophenyl)-2-propenyl] methylamino] methyl] phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide) and antennapedia autocamtide-related inhibitory peptide II is able to reverse both the alterations in corticostriatal synaptic plasticity and the deficits in spontaneous motor behavior that are found in an animal model of PD. The same beneficial effects are produced by a regimen of L-3,4-dihydroxyphenylalanine(L-DOPA) treatment, which is able to normalize alphaCaMKII autophosphorylation. These data indicate that abnormal alphaCaMKII autophosphorylation plays a causal role in the alterations of striatal plasticity and motor behavior that follow DA denervation. Normalization of CaMKII activity may be an important underlying mechanism of the therapeutic action of L-DOPA in PD.},
  author       = {Picconi, B and Gardoni, F and Centonze, D and Mauceri, D and Cenci Nilsson, Angela and Bernardi, G and Calabresi, P and Di Luca, M},
  issn         = {1529-2401},
  keyword      = {rat,LTP,CaMKII,6-OHDA,Parkinson's disease,striatum},
  language     = {eng},
  number       = {23},
  pages        = {5283--5291},
  publisher    = {Society for Neuroscience},
  series       = {Journal of Neuroscience},
  title        = {Abnormal Ca2+-calmodulin-dependent protein kinase II function mediates synaptic and motor deficits in experimental parkinsonism},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.1224-04.2004},
  volume       = {24},
  year         = {2004},
}