Subtype-Specific GABA Transporter Antagonists Synergistically Modulate Phasic and Tonic GABAAConductances in Rat Neocortex
Open Access
- 1 September 2005
- journal article
- research article
- Published by American Physiological Society in Journal of Neurophysiology
- Vol. 94 (3), 2073-2085
- https://doi.org/10.1152/jn.00520.2005
Abstract
GABAergic inhibition in the brain can be classified as either phasic or tonic. γ-Aminobutyric acid (GABA) uptake by GABA transporters (GATs) can limit the time course of phasic currents arising from endogenous and exogenous GABA, as well as decrease a tonically active GABA current. GABA transporter subtypes 1 and 3 (GAT-1 and GAT-3) are the most heavily expressed of the four known GAT subtypes. The role of GATs in shaping GABA currents in the neocortex has not been explored. We obtained patch-clamp recordings from layer II/III pyramidal cells and layer I interneurons in rat sensorimotor cortex. We found that selective GAT-1 inhibition with NO711 decreased the amplitude and increased the decay time of evoked inhibitory postsynaptic currents (IPSCs) but had no effect on the tonic current or spontaneous IPSCs (sIPSCs). GAT-2/3 inhibition with SNAP-5114 had no effect on IPSCs or the tonic current. Coapplication of NO711 and SNAP-5114 substantially increased tonic currents and synergistically decreased IPSC amplitudes and increased IPSC decay times. sIPSCs were not resolvable with coapplication of NO711 and SNAP-5114. The effects of the nonselective GAT antagonist nipecotic acid were similar to those of NO711 and SNAP-5114 together. We conclude that synaptic GABA levels in neocortical neurons are controlled primarily by GAT-1, but that GAT-1 and GAT-2/3 work together extrasynaptically to limit tonic currents. Inhibition of any one GAT subtype does not increase the tonic current, presumably as a result of increased activity of the remaining transporters. Thus neocortical GAT-1 and GAT-2/3 have distinct but overlapping roles in modulating GABA conductances.Keywords
This publication has 86 references indexed in Scilit:
- GABA Release and Uptake Regulate Neuronal Precursor Migration in the Postnatal Subventricular ZoneJournal of Neuroscience, 2004
- Slow phases of GABAA receptor desensitization: structural determinants and possible relevance for synaptic functionThe Journal of Physiology, 2002
- Cooperation between independent hippocampal synapses is controlled by glutamate uptakeNature Neuroscience, 2002
- Nipecotic acid directly activates GABAA -like ion channelsBritish Journal of Pharmacology, 2001
- Distinct Functional and Pharmacological Properties of Tonic and Quantal Inhibitory Postsynaptic Currents Mediated by γ-Aminobutyric AcidA Receptors in Hippocampal NeuronsPublished by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2001
- Adaptive regulation of neuronal excitability by a voltage- independent potassium conductanceNature, 2001
- TiagabineDrugs, 1998
- Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.The Journal of Physiology, 1996
- GABA TRANSPORTER HETEROGENEITY: PHARMACOLOGY AND CELLULAR LOCALIZATIONNeurochemistry International, 1996
- Quantitative Distribution of GABA-immunopositive and-immunonegative Neurons and Synapses in the Monkey Striate Cortex (Area 17)Cerebral Cortex, 1992