QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, June 9, 2004, 24(23):5283-5291; doi:10.1523/JNEUROSCI.1224-04.2004

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (21) Citing Articles via Google Scholar Google Scholar Articles by Picconi, B. Articles by Di Luca, M. Search for Related Content PubMed PubMed Citation Articles by Picconi, B. Articles by Di Luca, M.

 Previous Article  |  Next Article 

Neurobiology of Disease
Abnormal Ca²⁺-Calmodulin-Dependent Protein Kinase II Function Mediates Synaptic and Motor Deficits in Experimental Parkinsonism

Barbara Picconi,^1 * Fabrizio Gardoni,^2 * Diego Centonze,¹ Daniela Mauceri,² M. Angela Cenci,³ Giorgio Bernardi,¹ Paolo Calabresi,¹ and Monica Di Luca²

¹Clinica Neurologica, Dipartimento di Neuroscienze, Università di Roma Tor Vergata, 00133 Rome, Italy and Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, 00179 Rome, Italy, ²Center of Excellence on Neurodegenerative Diseases and Department of Pharmacological Sciences, University of Milano, 20133 Milan, Italy, and ³Wallenberg Neuroscience Centre, Neurobiology Division, Lund University, S 221 84 Lund, Sweden

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 Ca²⁺-calmodulin-dependent protein kinase II (CaMKII) autophosphorylation, along with a higher recruitment of activated CaMKII 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-benzazepine hydrochloride, but not with L-sulpiride, mimicked the effect of DA denervation on both CaMKII autophosphorylation and corticostriatal synaptic plasticity. In addition to normalizing CaMKII 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 CaMKII autophosphorylation. These data indicate that abnormal CaMKII 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.

Key words: 6-OHDA; Parkinson's disease; CaMKII; LTP; rat; striatum

---

Received Feb 23, 2004; revised April 27, 2004; accepted April 27, 2004.

This article has been cited by other articles:

				A. M. Brown, A. J. Baucum, M. A. Bass, and R. J. Colbran Association of Protein Phosphatase 1{gamma}1 with Spinophilin Suppresses Phosphatase Activity in a Parkinson Disease Model J. Biol. Chem., May 23, 2008; 283(21): 14286 - 14294. [Abstract] [Full Text] [PDF]

				F. Gardoni, B. Picconi, V. Ghiglieri, F. Polli, V. Bagetta, G. Bernardi, F. Cattabeni, M. Di Luca, and P. Calabresi A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. J. Neurosci., March 15, 2006; 26(11): 2914 - 2922. [Abstract] [Full Text] [PDF]

				C. Fiorentini, M. C. Rizzetti, C. Busi, S. Bontempi, G. Collo, P. Spano, and C. Missale Loss of Synaptic D1 Dopamine/N-Methyl-D-aspartate Glutamate Receptor Complexes in L-DOPA-Induced Dyskinesia in the Rat Mol. Pharmacol., March 1, 2006; 69(3): 805 - 812. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help