Figure 9.
Recurrent seizures invert the effects of GABAA receptors via NKCC1-dependent mechanism. a, Spontaneous seizures (Status Epilepticus) were induced by brief bath application of the GABAA receptor antagonist SR 95531 (SR; 10 μm). In the bottom, spontaneous epileptiform discharges are shown on an expanded timescale. b, c, Effects of the GABAA-R agonist isoguvacine (ISO) on MUA and spontaneous epileptiform activity. In control ACSF, application isoguvacine (10 μm) decreased the frequency of MUA. At 30–40 min after onset of spontaneous seizures, isoguvacine increased the frequency of MUA and interictal epileptiform discharges. Excitatory effects of isoguvacine on population activity persisted at least 1–2 h after termination of seizures. c, Bumetanide (10 μm) prevented the excitatory action of isoguvacine on the MUA and interictal epileptiform discharges. a–c, Extracellular recordings of MUA and population activity were performed in the CA3 pyramidal cell layer of intact neonatal (P4–P5) hippocampal preparations in vitro. d, e, Mean frequency of MUA in control ACSF and in the presence of bumetanide (BUM; n = 6) before, during, and after spontaneous seizures. d, Time course of isoguvacine action on MUA frequency. Bumetanide (10 μm) prevented the seizure-induced reversal of the effects of GABAA-R activation.