title: GABA transporter GAT1 prevents spillover at proximal and distal GABA synapses onto primate prefrontal cortex neurons.
abstract: The plasma membrane GABA transporter GAT1 is thought to mediate uptake of synaptically released GABA. In the primate dorsolateral prefrontal cortex (DLPFC), GAT1 expression changes significantly during development and in schizophrenia. The consequences of such changes, however, are not well understood because GAT1's role has not been investigated in primate neocortical circuits. We thus studied the effects of the GAT1 blocker 1,2,5,6-tetrahydro-1-[2-[[(diphenylmethylene)amino]oxy]ethyl]-3-pyridinecarboxylic acid hydrochloride (NO711) on GABA transmission onto pyramidal neurons of monkey DLPFC. As in rat cortex, in monkey DLPFC NO711 did not substantially alter miniature GABA transmission, suggesting that GAT1 does not regulate single-synapse transmission. In rat cortical circuits, between-synapse GABA spillover produced by NO711 clearly prolongs the inhibitory postsynaptic currents, but whether NO711 also prolongs the inhibitory postsynaptic potentials (IPSPs) is unclear. Moreover, whether spillover differentially affects perisomatic versus dendritic inputs has not been examined. Here we found that NO711 prolonged the GABAA receptor-mediated IPSPs (GABAAR-IPSPs) evoked by stimulating perisomatic synapses. Dendritic, but not perisomatic, synapse stimulation often elicited a postsynaptic GABAB receptor-mediated IPSP that was enhanced by NO711. Blocking GABAB receptors revealed that NO711 prolonged the GABAAR-IPSPs evoked by stimulation of dendrite-targeting inputs. We conclude that a major functional role for GAT1 in primate cortical circuits is to prevent the effects of GABA spillover when multiple synapses are simultaneously active. Furthermore, we report that, at least in monkey DLPFC, GAT1 similarly restricts GABA spillover onto perisomatic or dendritic inputs, critically controlling the spatiotemporal specificity of inhibitory inputs onto proximal or distal compartments of the pyramidal cell membrane.
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, W1651 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15261, USA. gburgos@pitt.edu
authors.forename: Guillermo
authors.initials: G
authors.lastname: Gonzalez-Burgos
authors.forename: Diana C
authors.initials: DC
authors.lastname: Rotaru
authors.forename: Aleksey V
authors.initials: AV
authors.lastname: Zaitsev
authors.forename: Nadezhda V
authors.initials: NV
authors.lastname: Povysheva
authors.forename: David A
authors.initials: DA
authors.lastname: Lewis
mesh_terms: D000818:Animals; D004558:Electric Stimulation; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins / Q000502:physiology*; D058805:GABA Uptake Inhibitors; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D008959:Models, Neurological; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009557:Nipecotic Acids / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D017397:Prefrontal Cortex / Q000166:cytology*; D011724:Pyridazines / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018755:GABA Agonists; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D058805:GABA Uptake Inhibitors; D009557:Nipecotic Acids; D009943:Organophosphorus Compounds; D010091:Oximes; D011724:Pyridazines; C078793:NNC 711; D005680:gamma-Aminobutyric Acid; C066430:CGP 35348; C049853:gabazine