~ Pergamon Neuroscience Vol. 76, No. 2, pp. 335 343, 1997 Copyright C~ 1996 IBRO. Published by ElsevierScienceLtd Printed in Great Britain PII: S0306-4522(96)00409-5 0306M522/97 $17.00+0.00 COMMENTARY RE-EVALUATION OF THE FUNCTIONAL ANATOMY OF THE BASAL GANGLIA IN NORMAL AND PARKINSONIAN STATES R. LEVY,* L.-N. HAZRATI,t M.-T. HERRERO,*$ M. VILA,* O.-K. HASSANI,§ M. MOUROUX,§ M. RUBERG,* H. ASENSI,:~ Y. AGID,* J. FEGER,§ J. A. OBESO,¶ A. PARENT t and E. C. HIRSCH*I *INSERM U. 289, H6pital de la Salp~tri+re, 47 bd de l'H6pital, 75651, Paris, Cedex 13, France tLaboratoire de Neurobiologie, LocalF-7500, Centre de Recherche Universit6 Larval Robert-Giffard, 2601 de la Canardibre, Beaufort, Quebec, Canada, G13 124 ++Departamento de Ciencias Morfol6gicas, University of Murcia, 30150 Murcia, Spain §Laboratoire de Pharmacologie, Universitd Rend Descartes, 4 avenue de l'observatoire, 75270 Paris Cedex 6, France ¶Centro de Neurologia y Neurocirurgia Funcional, Clinica Quiron, Parque Acolea, Sln 20012 San Sebastian, Spain Abstraet--ln the late 1980s, a functional and anatomical model of basal ganglia organization was proposed in order to explain the clinical syndrome of Parkinson's disease. According to this model, the pathological overactivity observed in the subthalamic nucleus and the output station of the basal ganglia plays a crucial role in the pathophysiology of the motor signs of Parkinson's disease. The hyperactivity of subthalamic neurons in Parkinsonism is viewed as a direct consequence of a pathological hypoactivity of the external segment of the pallidum. This article reviews recent data from different experimental approaches that challenge the established model of basal ganglia organization by reinterpreting the functional interaction between the external segment of the pallidum and the subthalamic nucleus in both the normal and pathological state. Indeed, recent neurobiochemical studies have rather unexpectedly shown that the GABAergic and metabolic activities of the external pallidum are not decreased in human and non-human primates with Parkinsonism. This absence of any decrease in activity might be explained by the functionally antagonistic influences of the striatal and subthalamic afferences within the external pallidum, as suggested by several anatomical studies. In addition, there are clues from electrophysiological studies to suggest that the hyperactivity found in the subthalamic neurons in Parkinsonism may not depend solely on the level of activity in the external pallidum. In such a framework, the hyperactivity of the subthalamic neurons would have to be explained, at least in part, by other sources of excitation or disinhibition. However, any explanation for the origin of the subthalamic overactivity in Parkinsonism remains speculative. Copyright ~ 1996 IBRO. Published by Elsevier Science Ltd. Key words: Parkinson's disease, 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, glutamate decarboxylase, cytochrome oxidase, pallidum, subthalamic nucleus. An accurate knowledge of the anatomical and func- tional organization of the basal ganglia is an essential step in improving our understanding of how motor and cognitive functions operate in the normal brain. ITo whom correspondence should be addressed. Abbreviations: CO, cytochrome oxidase; 2-DG, 2-deoxyglucose: GAD, glutamate decarboxylase; GPe, external segrnfa~ of the pallidum; GPi, internal segment of the pallidum; MPTP, 1-methyl-4-phenyl-l,2,3,6- tetrahydropyridine; 6-OHDA, 6-hydroxydopamine; PD, Parkinson's disease; Pf nucleus, parafascicular nucleus; QISH, quantitative in situ hybridization; SNpc, substan- tia nigra pars compacta; SNpr, substantia nigra pars reticulata; STN, subthalamic nucleus. There is also a fundamental need to clarify the consequences of the pathophysiological charrges that occur in Parkinson's disease (PD) and other disorders of the basal ganglia. In the late 1980s an elegant model was developed which proposed a framework for the anatomical organization of the basal ganglia and provided consistent explanations for the clinical syndrome of PD. 1,9~66 Subsequently, new therapeutic approaches to basal ganglia disorders were proposed. According to the model, the basal ganglia are organ- ized in such a fashion that nigrostriatal denervation (the hallmark of PD), experimentally produced by intoxication with 1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine (MPTP) in non-human primate 335