Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Dependovirus / genetics
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Disease Models, Animal
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Dopamine / metabolism
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Electric Stimulation
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Electrophysiology
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Genetic Therapy*
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Genetic Vectors
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Glutamate Decarboxylase / genetics*
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Glutamate Decarboxylase / metabolism
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Glutamic Acid / metabolism
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Humans
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Ibotenic Acid / pharmacology
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Isoenzymes / genetics*
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Isoenzymes / metabolism
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Male
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Mesencephalon / metabolism
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Mesencephalon / pathology
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Mice
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Motor Activity / drug effects
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Nerve Degeneration
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Neurons / metabolism*
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Oxidopamine / pharmacology
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Parkinsonian Disorders / metabolism
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Parkinsonian Disorders / pathology
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Parkinsonian Disorders / therapy*
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Phenotype
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Rats
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Stem Cells / virology
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Substantia Nigra / metabolism*
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Substantia Nigra / pathology
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Substantia Nigra / physiopathology
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Subthalamic Nucleus / metabolism*
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Subthalamic Nucleus / pathology
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Synaptic Transmission
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Transgenes
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gamma-Aminobutyric Acid / metabolism
Substances
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Isoenzymes
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Ibotenic Acid
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Glutamic Acid
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gamma-Aminobutyric Acid
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Oxidopamine
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Glutamate Decarboxylase
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glutamate decarboxylase 1
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glutamate decarboxylase 2
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Dopamine