Abstract
We report that half striatal cholinergic interneurons are dual transmitter cholinergic and GABAergic interneurons (CGINs) expressing ChAT, GAD65, Lhx7, and Lhx6 mRNAs, labeled with GAD and VGAT, generating monosynaptic dual cholinergic/GABAergic currents and an inhibitory pause response. Dopamine deprivation increases CGINs ongoing activity and abolishes GABAergic inhibition including the cortico-striatal pause because of high [Cl-]i levels. Dopamine deprivation also dramatically increases CGINs dendritic arbors and monosynaptic interconnections probability, suggesting the formation of a dense CGINs network. The NKCC1 chloride importer antagonist bumetanide, which reduces [Cl-]i levels, restores GABAergic inhibition, the cortico-striatal pause-rebound response, and attenuates motor effects of dopamine deprivation. Therefore, most of the striatal cholinergic excitatory drive is balanced by a concomitant powerful GABAergic inhibition that is impaired by dopamine deprivation. The attenuation by bumetanide of cardinal features of Parkinson's disease paves the way to a novel therapeutic strategy based on a restoration of low [Cl-]i levels and GABAergic inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / metabolism
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Acetylcholine / pharmacology
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Action Potentials / drug effects
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Action Potentials / physiology
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Animals
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Bumetanide / pharmacology
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Chlorides / metabolism
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Cholinergic Agents / metabolism
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Cholinergic Agents / pharmacology
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Cholinergic Neurons / drug effects
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Cholinergic Neurons / metabolism*
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Cholinergic Neurons / pathology
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism*
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Corpus Striatum / pathology
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Dopamine / deficiency
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Gene Expression Regulation
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Glutamate Decarboxylase / genetics
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Glutamate Decarboxylase / metabolism
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Humans
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Inhibitory Postsynaptic Potentials / drug effects*
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Interneurons / drug effects
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Interneurons / metabolism*
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Interneurons / pathology
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Ion Transport
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LIM-Homeodomain Proteins / genetics
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LIM-Homeodomain Proteins / metabolism
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Mice
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Mice, Transgenic
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Neuronal Plasticity / drug effects
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Parkinson Disease, Secondary / genetics
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Parkinson Disease, Secondary / metabolism*
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Parkinson Disease, Secondary / pathology
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Patch-Clamp Techniques
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Sodium Potassium Chloride Symporter Inhibitors / pharmacology
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Solute Carrier Family 12, Member 2 / genetics
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Solute Carrier Family 12, Member 2 / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Vesicular Inhibitory Amino Acid Transport Proteins / genetics
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Vesicular Inhibitory Amino Acid Transport Proteins / metabolism
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gamma-Aminobutyric Acid / metabolism*
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gamma-Aminobutyric Acid / pharmacology
Substances
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Chlorides
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Cholinergic Agents
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LHX6 protein, mouse
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LIM homeobox protein 8
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LIM-Homeodomain Proteins
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Nerve Tissue Proteins
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Slc12a2 protein, mouse
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Sodium Potassium Chloride Symporter Inhibitors
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Solute Carrier Family 12, Member 2
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Transcription Factors
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Vesicular Inhibitory Amino Acid Transport Proteins
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Viaat protein, mouse
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Bumetanide
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gamma-Aminobutyric Acid
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Glutamate Decarboxylase
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glutamate decarboxylase 2
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Acetylcholine
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Dopamine