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438 nature neuroscience volume 6 no 5 may 2003 itive stimulation. However, a burst of high-frequency stimulation can markedly enhance the response to subsequent low- frequency pulses, a change known as long- term potentiation 13 (LTP) that can last for a period of hours. LTP is widely consid- ered to be a cellular model of learning. In the striatum, LTP depends on activation of striatal dopamine synapses, as it is blocked by dopamine receptor blockade and by lesions of the endogenous dopamine pathway 6 . Picconi et al. 4 found that dopamine-dependent LTP was restored in lesioned animals by chronic treatment with low doses of L-DOPA ( Fig. 1b ), whether or not the animals exhibited dyskinesia. Although establishing new associa- tions is important, if learning is to be adaptive, the ability to ‘forget’ or ‘ignore’ irrelevant associations is also key. One mechanism for such regulation in LTP is depotentiation, whereby several minutes of low-frequency stimulation can abol- ish the potentiation provided by the high-frequency burst in the initial estab- lishment of LTP ( Fig. 1c ). In the current study, whereas L-DOPA restored LTP, including depotentiation, in the animals that did not develop dyskinesia, depo- tentiation was not induced in dyskinetic animals ( Fig. 1d ). Therefore, L-DOPA- induced dyskinesia is associated with (and perhaps results from) abnormal regulation of LTP in the striatum. those that do not develop dyskinesias would facilitate the identification of novel strate- gies to maintain or restore normal physio- logical plasticity in the striatum during L-DOPA treatment and optimize the effica- cy of the drug as a dyskinesia-free therapy for Parkinson’s disease. L.M. New Engl. J. Med. 282 , 31–33 (1967). 2. Poewe, W. & Granata, R. in Movement Disorders. Neurological Principles and Practice (McGraw-Hill, New York, 1997). 3. Obeso, J.A., Olanow, C.W. & Nutt, J.G. Trends Neurosci. 23 (Suppl.), S2–S7 (2000). 4. Picconi, B. et al. Nat. Neurosci. 6 , 501–506 (2003). 5. Dunnett, S.B. & Robbins, T.W. Biol. Rev. 67 , 491–518 (1992). 6. Centonze, D. et al. J. Neurophysiol. 82 , 3575–3579 (1999). 7. Zigmond, M. J., Abercrombie, E. D., Berger, T.W., Grace, A.A. & Stricker, E. M. Trends Neurosci. 13 , 290–296 (1990). 8. Ungerstedt, U. Acta Physiol. Scand. 367 (Suppl.), 69–93 (1971). 9. Bédard, P.J. et al. Mov. Disord. 14 (Suppl. 1), 4–8 (1999). Bernardi, G. Ann. Neurol. 47 (4 Suppl. 1), S60–S68, discussion S68–69 (2000). 11. Lundblad, M. et al. Eur. J. Neurosci. 15 , 120–132 (2002). 12. Cenci, M.A., Lee, C. S. & Björklund, A.
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