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The Journal of Neuroscience, September 6, 2006, 26(36):9323-9331; doi:10.1523/JNEUROSCI.2610-06.2006

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Cellular/Molecular
Deletion of the GABA_A Receptor 1 Subunit Increases Tonic GABA_A Receptor Current: A Role for GABA Uptake Transporters

Pavel I. Ortinski,^1,2 Jill R. Turner,^1,3 Andrea Barberis,² Gholam Motamedi,⁴ Robert P. Yasuda,^1,3 Barry B. Wolfe,^1,3 Kenneth J. Kellar,^1,3 and Stefano Vicini^1,2

¹Interdisciplinary Program in Neuroscience and Departments of Physiology and Biophysics, ³Pharmacology, and ⁴Neurology, Georgetown University School of Medicine, Washington, DC 20007

Correspondence should be addressed to Dr. Stefano Vicini, Department of Physiology and Biophysics, BSB225, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20007. Email: svicin01{at}georgetown.edu

The loss of more than half the number of GABA_A receptors yet lack of pronounced phenotype in mice lacking the gene for the GABA_A 1 subunit is somewhat paradoxical. We explored the role of tonic GABA_A receptor-mediated current as a target of compensatory regulation in the 1 knock-out (–/–) mice. A 62% increase of tonic current was observed in the cerebellar granule cells (CGCs) of 1^–/– compared with wild-type (+/+) mice along with a 67% increase of baseline current variance. Examination of whole-cell currents evoked by low concentrations of GABA and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol suggested no upregulation of 6 and subunit-containing GABA_A receptors in the 1^–/–, confirming previous biochemical studies. Single-channel current openings were on average 32% shorter in the 1^–/– neurons. Single-channel conductance and frequency of opening were not different between genotypes. Tonic current induced by application of the GABA transporter GAT-1 blocker NO711 (1-[2([(diphenylmethylene)imino]oxy)ethyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride) was significantly larger in the 1^–/–, suggesting an increase of ambient GABA concentration. Experiments done with a known concentration of extracellular GABA complemented by a series of biochemical experiments revealed a reduction of GAT activity in 1^–/– without an identifiable reduction of GAT-1 or GAT-3 protein. We report increased tonic GABA_A receptor-mediated current in the 1^–/– CGCs as a novel compensatory mechanism. Our data establish a role for GABA transporters as regulators of neuronal excitability in this and relevant models and examine other tonic conductance-regulating mechanisms responsible for the adaptive response of the cerebellar network to a deletion of a major synaptic GABA_A receptor subunit.

Key words: GABA_A; 1; knock-out; tonic inhibition; GABA transporter; patch-clamp

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Received Dec. 16, 2005; revised Aug. 3, 2006; accepted Aug. 4, 2006.

Correspondence should be addressed to Dr. Stefano Vicini, Department of Physiology and Biophysics, BSB225, Georgetown University School of Medicine, 3900 Reservoir Road, Washington, DC 20007. Email: svicin01{at}georgetown.edu

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