GABA transporter 1 tunes GABAergic synaptic transmission at output neurons of the mouse neostriatum.
GABAergic medium-sized striatal output neurons (SONs) provide the principal output for the neostriatum. In vitro and in vivo data indicate that spike discharge of SONs is tightly controlled by effective synaptic inhibition. Although phasic GABAergic transmission critically depends on ambient GABA levels, the role of GABA transporters (GATs) in neostriatal GABAergic synaptic transmission is largely unknown. In the present study we aimed at elucidating the role of GAT-1 in the developing mouse neostriatum (postnatal day (P) 7-34). We recorded GABAergic postsynaptic currents (PSCs) using the whole-cell patch-clamp technique. Based on the effects of NO-711, a specific GAT-1 blocker, we demonstrate that GAT-1 is operative at this age and influences GABAergic synaptic transmission by presynaptic and postsynaptic mechanisms. Presynaptic GABA(B)R-mediated suppression of GABA release was found to be functional at all ages tested; however, there was no evidence for persistent GABA(B)R activity under control conditions, unless GAT-1 was blocked (P12-34). In addition, whereas no tonic GABA(A)R-mediated conductances were detected in SONs until P14, application of a specific GABA(A)R antagonist caused distinct tonic outward currents later in development (P19-34). In the presence of NO-711, tonic GABA(A)R-mediated currents were also observed at P7-14 and were dramatically increased at more mature stages. Furthermore, GAT-1 block reduced the median amplitude of GABAergic miniature PSCs indicating a decrease in quantal size. We conclude that in the murine neostriatum GAT-1 operates in a net uptake mode. It prevents the persistent activation of presynaptic GABA(B)Rs (P12-34) and prevents (P7-14) or reduces (P19-34) tonic postsynaptic GABA(A)R activity.
Kirmse
Knut
K
Institute of Neurophysiology, Johannes Müller Centre of Physiology, Charité - University Medicine Berlin, Tucholskystr. 2, 10117 Berlin, Germany. knut.kirmse@charite.de
Dvorzhak
Anton
A
Kirischuk
Sergei
S
Grantyn
Rosemarie
R
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D017097:Electric Impedance; D004558:Electric Stimulation; D004594:Electrophysiology; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000166:cytology / Q000254:growth & development* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010721:Phosphinic Acids / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000502:physiology; D011412:Propanolamines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D018079:Receptors, GABA / Q000502:physiology*; D011963:Receptors, GABA-A / Q000502:physiology; D018080:Receptors, GABA-B / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D009557:Nipecotic Acids; D010091:Oximes; D010721:Phosphinic Acids; D011412:Propanolamines; D011724:Pyridazines; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; C078793:NNC 711; C085075:CGP 55845A; C017069:bicuculline methiodide; D013779:Tetrodotoxin; C049853:gabazine; D001418:Baclofen; D001640:Bicuculline