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The Journal of Neuroscience, September 10, 2003, 23(23):8237-8246

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Cell Type-Specific Differences in Chloride-Regulatory Mechanisms and GABA_A Receptor-Mediated Inhibition in Rat Substantia Nigra

Alexandra Gulácsi,^1,2 * Christian R. Lee,^3 * Attila Sík,^1,4 Tero Viitanen,⁵ Kai Kaila,⁵ James M. Tepper,³ and Tamás F. Freund¹

¹Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, H-1083 Hungary, ²Department of Neurobiology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, ³Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, New Jersey 07102, ⁴Centre de Recherche Université Laval Robert-Giffard, Quebec City, Quebec G1J 2G3 Canada, and ⁵Department of Biosciences, Division of Animal Physiology, University of Helsinki, Helsinki 00014, Finland

The regulation of intracellular chloride has important roles in neuronal function, especially by setting the magnitude and direction of the Cl^- flux gated by GABA_A receptors. Previous studies have shown that GABA_A-mediated inhibition is less effective in dopaminergic than in GABAergic neurons in substantia nigra. We studied whether this phenomenon may be related to a difference in Cl-regulatory mechanisms. Light-microscopic immunocytochemistry revealed that the potassium-chloride cotransporter 2 (KCC2) was localized only in the dendrites of nondopaminergic (primarily GABAergic) neurons in the substantia nigra, whereas the voltage-sensitive chloride channel 2 (ClC-2) was observed only in the dopaminergic neurons of the pars compacta. Electron-microscopic immunogold labeling confirmed that KCC2 is localized in the dendritic plasma membrane of GABAergic neurons close to inhibitory synapses. Confocal microscopy showed that ClC-2 was selectively expressed in the somatic and dendritic cell membranes of the dopaminergic neurons. Gramicidin-perforated-patch recordings revealed that the GABA_A IPSP reversal potential was significantly less negative and had a much smaller hyperpolarizing driving force in dopaminergic than in GABAergic neurons. The GABA_A reversal potential was significantly less negative in bicarbonate-free buffer in dopaminergic but not in GABAergic neurons. The present study suggests that KCC2 is responsible for maintaining the low intracellular Cl^- concentration in nigral GABAergic neurons, whereas a sodium-dependent anion (Cl^--HCO₃^-) exchanger and ClC-2 are likely to serve this role in dopaminergic neurons. The relatively low efficacy of GABA_A-mediated inhibition in nigral dopaminergic neurons compared with nigral GABAergic neurons may be related to their lack of KCC2.

Key words: substantia nigra; chloride regulation; dopaminergic neurons; GABAergic neurons; potassium-chloride cotransporters; chloride channels

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Received May 5, 2003; revised June 24, 2003; accepted July 2, 2003.

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