The GABA Transporters GAT-1 and GAT-3 modulate glutamatergic transmission via activation of presynaptic GABAB receptors in the rat globus pallidus

• Authors: Xiao-Tao Jin, Emory University; Jean-Francois Pare, Emory University; Yoland Smith, Emory University
• Journal Title: European Journal of Neuroscience
• Volume: Volume 36, Number 4
• Publisher: Wiley: 12 months | 2012-08, Pages 2482-2492
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1111/j.1460-9568.2012.08147.x
• Subjects: Biology, Neuroscience
• Keywords: EPSC; patch-clamp; striatum; GATs; GABA receptor

Abstract

Intrapallidal application of GAT-1 or GAT-3 transporter blockers (SKF 89976A or SNAP 5114) reduces the activity of pallidal neurons in monkey. This effect could be mediated through activation of presynaptic GABAB heteroreceptors in glutamatergic terminals by GABA spillover following GABA transporters (GATs) blockade. To test this hypothesis, we applied the whole-cell recording technique to study the effects of SKF 89976A and SNAP 5114 on evoked excitatory post synaptic currents (eEPSCs) in presence of gabazine, a GABAA receptor antagonist, in rat GP slice preparations. Under the condition of postsynaptic GABAB receptor blockade by intracellular application of OX314, bath application of SKF 89976A (10 μM) or SNAP 5114 (10 μM) decreased the amplitude of eEPSCs, without significant effect on its holding current and whole cell input resistance. The inhibitory effect of GATs blockade on eEPSCs was blocked by CGP 58845, a GABAB receptor antagonist. The paired-pulse ratio (PPR) of evoked EPSCs was increased, while the frequency, but not the amplitude, of miniature excitatory postsynaptic currents (mEPSCs) was reduced in presence of either GAT blockers, demonstrating a presynaptic effect. These results suggest that synaptically released GABA can inhibit glutamatergic transmission through activation of presynaptic GABAB heteroreceptors following GAT-1 or GAT-3 blockade. In conclusion, our findings demonstrate that pre-synaptic GABAB heteroreceptors in putative glutamatergic subthalamic afferents to GP are sensitive to increases in extracellular GABA induced by GATs inactivation, thereby suggesting that GATs blockade represents a potential mechanism by which overactive subthalamopallidal activity may be reduced in parkinsonism.