Recurrent neonatal seizures increase tonic inhibition and respond to enhancers of δ-containing GABAA receptors

Abstract

About one-third of neonatal seizures do not respond to the first-line anticonvulsant phenobarbital, which activates phasic inhibition and whose effectiveness decreases over time. Whether enhancing tonic inhibition can treat refractory seizures or status epilepticus in neonates remains uncertain. We evaluated the effect of recurrent seizure-like events (SLE) on α5– and δ–GABAA receptor (α5- and δ-GABAA R) subunit expression and tonic inhibition in neonatal C57BL/6J mice (P6–9, both sexes) using acute brain slices. We investigated the impact of THIP (gaboxadol) on neonatal behavioral seizures, neuronal apoptosis, and neurodegeneration in vivo. We found neonatal neocortical expression of α5- and δ-GABAA R subunits. Blocking α5-GABAA Rs with L-655,708 did not affect acute neonatal SLE, whereas enhancing δ-GABAA Rs with THDOC, a neurosteroid, reduced them. The α5- and δ-GABAA R membrane expression increased after 8 hours of neonatal SLE and correlated with increased δ-mediated conductance but not α5-mediated conductance. Enhancing tonic inhibition was more effective in reducing recurrent neonatal SLE (8 hours) compared with early treatment. Increasing tonic inhibition reduced the duration, severity, and number of kainic acid induced in vivo neonatal behavioral seizures without increasing neurodegeneration or apoptosis. We conclude that recurrent neonatal seizures increase tonic inhibition. Therefore, enhancing tonic inhibition may be a treatment strategy for prolonged neonatal status epilepticus.