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The Journal of Neuroscience, December 24, 2008, 28(52):14245-14258; doi:10.1523/JNEUROSCI.4199-08.2008

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Neurobiology of Disease
Parkinsonian Beta Oscillations in the External Globus Pallidus and Their Relationship with Subthalamic Nucleus Activity

Nicolas Mallet,^1,2 Alek Pogosyan,² László F. Márton,^1,3 J. Paul Bolam,¹ Peter Brown,² and Peter J. Magill¹

¹Medical Research Council Anatomical Neuropharmacology Unit, University of Oxford, Oxford OX1 3TH, United Kingdom, ²Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, London WC1N 3BG, United Kingdom, and ³Neural Systems Research Group, Sapientia–Hungarian University of Transylvania, 540485 Târgu-Mure, Romania

Correspondence should be addressed to either of the following: Dr. Peter J. Magill or Dr. Nicolas Mallet, Medical Research Council Anatomical Neuropharmacology Unit, University of Oxford, Mansfield Road, Oxford OX1 3TH, UK. Email: peter.magill{at}pharm.ox.ac.uk or Email: nicolas.mallet{at}pharm.ox.ac.uk

Inappropriately synchronized beta (β) oscillations (15–30 Hz) in the subthalamic nucleus (STN) accompany movement difficulties in idiopathic Parkinson's disease (PD). The cellular and network substrates underlying these exaggerated β oscillations are unknown but activity in the external globus pallidus (GP), which forms a candidate pacemaker network with STN, might be of particular importance. Using a clinically relevant rat model of PD, we demonstrate that oscillatory activity in GP neuronal networks becomes excessively and selectively synchronized at β frequencies in a spatially widespread and brain state-dependent manner after lesion of dopamine neurons. Although synchronization of GP unit activity increased by almost 100-fold during β oscillations, the mean firing rate of GP neurons decreased compared with controls. Importantly, in parkinsonian animals, two main types of GP neuron were identified according to their distinct and inversely related firing rates and patterns. Moreover, neurons of the same type tended to fire together, with small phase differences, whereas different types of neuron tended not to do so. This functional dichotomy in temporal coupling persisted across extreme brain states, suggesting that maladaptive interactions are dominated by hardwiring. Finally, the precisely timed discharges of GP and STN neurons indicated that rhythmic sequences of recurrent excitation and inhibition in the STN-GP network, and lateral inhibition between GP neurons, could actively support abnormal β oscillations. We propose that GP neurons, by virtue of their spatiotemporal synchronization, widespread axon collaterals and feed-back/feed-forward mechanisms, are well placed to orchestrate and propagate exaggerated β oscillations throughout the entire basal ganglia in PD.

Key words: globus pallidus; subthalamic nucleus; basal ganglia; Parkinson's disease; dopamine; 6-hydroxydopamine

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Received Sept. 3, 2008; revised Nov. 11, 2008; accepted Nov. 13, 2008.

Correspondence should be addressed to either of the following: Dr. Peter J. Magill or Dr. Nicolas Mallet, Medical Research Council Anatomical Neuropharmacology Unit, University of Oxford, Mansfield Road, Oxford OX1 3TH, UK. Email: peter.magill{at}pharm.ox.ac.uk or Email: nicolas.mallet{at}pharm.ox.ac.uk

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