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 The 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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/275240
- author
- Picconi, B
; Gardoni, F
; Centonze, D
; Mauceri, D
; Cenci Nilsson, Angela
LU
; Bernardi, G
; Calabresi, P
and Di Luca, M
- organization
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- rat, LTP, CaMKII, 6-OHDA, Parkinson's disease, striatum
- in
- The Journal of Neuroscience
- volume
- 24
- issue
- 23
- pages
- 5283 - 5291
- publisher
- Society for Neuroscience
- external identifiers
-
- pmid:15190099
- wos:000221924800001
- scopus:2942586826
- pmid:15190099
- 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
- 2016-04-01 16:59:10
- date last changed
- 2023-09-05 04:55:17
@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}},
keywords = {{rat; LTP; CaMKII; 6-OHDA; Parkinson's disease; striatum}},
language = {{eng}},
number = {{23}},
pages = {{5283--5291}},
publisher = {{Society for Neuroscience}},
series = {{The 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}},
doi = {{10.1523/JNEUROSCI.1224-04.2004}},
volume = {{24}},
year = {{2004}},
}