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The Journal of Neuroscience, August 2, 2006, 26(31):8101-8114; doi:10.1523/JNEUROSCI.5140-05.2006

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Neurobiology of Disease
Dopamine Replacement Therapy Does Not Restore the Full Spectrum of Normal Pallidal Activity in the 1-Methyl-4-Phenyl-1,2,3,6-Tetra-Hydropyridine Primate Model of Parkinsonism

Gali Heimer,^1,4 Michal Rivlin-Etzion,^1,2 Izhar Bar-Gad,⁵ Joshua A. Goldberg,⁶ Suzanne N. Haber,⁷ and Hagai Bergman^1,2,3

¹Department of Physiology, ²Interdisciplinary Center for Neural Computation, and ³Eric Roland Center for Neurodegenerative Diseases, The Hebrew University–Hadassah Medical School, Jerusalem, Israel, 91120, ⁴Department of Pediatrics, Hadassah–Hebrew University Medical Center, Jerusalem, Israel, 91120, ⁵Gonda Brain Research Center, Bar-Ilan University, Ramat-Gan, Israel, 52900, ⁶Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249, and ⁷Department of Pharmacology and Physiology, University of Rochester, Rochester, New York 14642

Correspondence should be addressed to Gali Heimer, Department of Physiology, The Hebrew University–Hadassah Medical School, P.O. Box 12272, Jerusalem, Israel 91120. Email: galih{at}md.huji.ac.il

Current physiological studies emphasize the role of neuronal oscillations and synchronization in the pathophysiology of Parkinson’s disease; however, little is known about their specific roles in the neuronal substrate of dopamine replacement therapy (DRT). We investigated oscillatory activity and correlations throughout the different states of levodopa-naive parkinsonism as well as "Off–On" and dyskinetic states of DRT in the external globus pallidum (GPe) of tremulous (vervet) and rigid-akinetic (macaque) monkeys and in the internal globus pallidum (GPi) of the vervet monkey. We found that, although oscillatory activity of cells and interneuronal correlation in both pallidal segments increases after induction of parkinsonism with 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) and decreases in response to DRT, important differences exist between the two pallidal segments. In the GPi, the fraction of oscillatory cells and relative power of oscillations were significantly higher than in the GPe, and the dominant frequency was within the range of 7.5–13.5 Hz compared with a range of 4.5–7.5 Hz within the GPe. The interneuronal correlations were mostly oscillatory in the GPi, whereas at least half are non-oscillatory in the GPe. We demonstrate that the tremor characteristics after exposure to DRT do not resemble those of the normal or the levodopa-naive state. Moreover, although DRT reverses the MPTP-induced neuronal changes (rate, pattern, and pairwise correlations), the balance between GPe and GPi fails to restore. We therefore suggest that this imbalance reflects additional abnormal organization of the basal ganglia networks in response to dopamine replacement and may constitute the physiological substrate of the limitations and side effects of chronic DRT.

Key words: Parkinson’s disease; basal ganglia; MPTP; tremor; cross-correlations; levodopa

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Received May 2, 2005; revised June 9, 2006; accepted June 10, 2006.

Correspondence should be addressed to Gali Heimer, Department of Physiology, The Hebrew University–Hadassah Medical School, P.O. Box 12272, Jerusalem, Israel 91120. Email: galih{at}md.huji.ac.il

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