Impairment of GABA transporter GAT-1 terminates cortical recurrent network activity via enhanced phasic inhibition

• Main Authors: Daniel Simon Razik, David Johannes Hawellek, Bernd eAntkowiak, Harald eHentschke
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2013-09-01
• Series: Frontiers in Neural Circuits
• Subjects: Neocortex; gaba receptor; tonic inhibition; GABA transporter; spillover; GABA reuptake
• Online Access: http://journal.frontiersin.org/Journal/10.3389/fncir.2013.00141/full

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 towards 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.