Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus

Status epilepticus (SE) is a common neurological emergency that results from the failure of the mechanisms responsible for seizure termination or the initiation of mechanisms that lead to abnormally prolonged seizures. Although the failure of inhibitory mechanisms during SE is well understood, the seizure-initiating mechanisms are poorly understood. We tested whether hippocampal alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission was enhanced during SE and assessed the underlying molecular mechanism. In animals in self-sustaining limbic SE the amplitudes of the miniature, spontaneous, and AMPAevoked excitatory currents recorded from the CAl pyramidal neurons were larger than those recorded in the controls. The evoked EPSCs rectified inwardly. In these animals, the surface expression of GluAl subunit-containing AMPARs was increased in the CA1 pyramidal neurons. The phosphorylation of the GluAl subunit on 5831 and S845 residues was reduced in animals in SE. In contrast, the GluAl subunit surface expression and AMPAR-mediated neurotransmission of dentate granule cells (DGCs) was not altered. Treating animals in SE with the NMDAR antagonist MK-801 or with diazaepam blocked the increased surface expression of the GluAl subunits. NMDAR blockade also prevented the dephosphorylation of the 5845 residue but not that of 5831. Targeting NMDARs and AMPARs may provide novel strategies to treat benzodiazepine-refractory SE. (C) 2017 Elsevier Inc. All rights reserved.