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Science 298 (5592): 425-429

Copyright © 2002 by the American Association for the Advancement of Science

Subthalamic GAD Gene Therapy in a Parkinson's Disease Rat Model

Jia Luo,12 Michael G. Kaplitt,3 Helen L. Fitzsimons,1* David S. Zuzga,2 Yuhong Liu,2 Michael L. Oshinsky,2 Matthew J. During12dagger

The motor abnormalities of Parkinson's disease (PD) are caused by alterations in basal ganglia network activity, including disinhibition of the subthalamic nucleus (STN), and excessive activity of the major output nuclei. Using adeno-associated viral vector-mediated somatic cell gene transfer, we expressed glutamic acid decarboxylase (GAD), the enzyme that catalyzes synthesis of the neurotransmitter GABA, in excitatory glutamatergic neurons of the STN in rats. The transduced neurons, when driven by electrical stimulation, produced mixed inhibitory responses associated with GABA release. This phenotypic shift resulted in strong neuroprotection of nigral dopamine neurons and rescue of the parkinsonian behavioral phenotype. This strategy suggests that there is plasticity between excitatory and inhibitory neurotransmission in the mammalian brain that could be exploited for therapeutic benefit.

1 Functional Genomics and Translational Neuroscience Laboratory, Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
2 CNS Gene Therapy Center, Jefferson Medical College, Philadelphia, PA 19107, USA.
3 Center for Stereotactic and Functional Neurosurgery, Department of Neurological Surgery, Weill Medical College of Cornell University, New York, NY 10021, USA.
*   Present address: Neurologix Inc., Delaware Biotechnology Institute, 15 Innovation Way, Newark, DE 19711, USA.

dagger    To whom correspondence should be addressed. E-mail: m.during{at}

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