Impairment of GABA transporter GAT-1 terminates cortical recurrent network activity via enhanced phasic inhibition.
In the central nervous system, GABA transporters (GATs) very efficiently clear synaptically released GABA from the extracellular space, and thus exert a tight control on GABAergic inhibition. In neocortex, GABAergic inhibition is heavily recruited during recurrent phases of spontaneous action potential activity which alternate with neuronally quiet periods. Therefore, such activity should be quite sensitive to minute alterations of GAT function. Here, we explored the effects of a gradual impairment of GAT-1 and GAT-2/3 on spontaneous recurrent network activity--termed network bursts and silent periods--in organotypic slice cultures of rat neocortex. The GAT-1 specific antagonist NO-711 depressed activity already at nanomolar concentrations (IC50 for depression of spontaneous multiunit firing rate of 42 nM), reaching a level of 80% at 500-1000 nM. By contrast, the GAT-2/3 preferring antagonist SNAP-5114 had weaker and less consistent effects. Several lines of evidence pointed toward an enhancement of phasic GABAergic inhibition as the dominant activity-depressing mechanism: network bursts were drastically shortened, phasic GABAergic currents decayed slower, and neuronal excitability during ongoing activity was diminished. In silent periods, NO-711 had little effect on neuronal excitability or membrane resistance, quite in contrast to the effects of muscimol, a GABA mimetic which activates GABAA receptors tonically. Our results suggest that an enhancement of phasic GABAergic inhibition efficiently curtails cortical recurrent activity and may mediate antiepileptic effects of therapeutically relevant concentrations of GAT-1 antagonists.
Experimental Anesthesiology Section, Department of Anesthesiology, University Hospital of Tübingen Tübingen, Germany.
Daniel S
DS
Razik
David J
DJ
Hawellek
Bernd
B
Antkowiak
Harald
H
Hentschke
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D005260:Female; D050485:GABA Plasma Membrane Transport Proteins / Q000378:metabolism*; D008297:Male; D019579:Neocortex / Q000187:drug effects* / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects* / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology; D009557:Nipecotic Acids / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D051381:Rats; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C092337:1-(2-(tris(4-methoxyphenyl)methoxy)ethyl)-3-piperidinecarboxylic acid; D000840:Anisoles; D050485:GABA Plasma Membrane Transport Proteins; D014179:Neurotransmitter Uptake Inhibitors; D009557:Nipecotic Acids; D010091:Oximes; C078793:NNC 711; D005680:gamma-Aminobutyric Acid
GABA receptor; GABA reuptake; GABA transporter; NO-711; SNAP-5114; phasic inhibition; spillover; tonic inhibition