Rapid surface accumulation of NMDA receptors increases glutamatergic excitation during status epilepticus

After 1 h of lithium-pilocarpine status epilepticus (SE), immunocytochemical labeling of NMDA receptor NR1 subunits reveals relocation of subunits from the interior to the cell surface of dentate gyrus granule cells and CA3 pyramidal cells. Simultaneously, an increase in NMDA-miniature excitatory postsynaptic currents (mEPSC) as well as an increase in NMDA receptor-mediated tonic currents is observed in hippocampal slices after SE. Mean-variance analysis of NMDA-mEPSCs estimates that the number of functional postsynaptic NMDA receptors per synapse increases 38% during SE, and antagonism by ifenprodil suggests that an increase in the surface representation of NR2B-containing NMDA receptors is responsible for the augmentation of both the phasic and tonic excitatory currents with SE. These results provide a potential mechanism for an enhancement of glutamatergic excitation that maintains SE and may contribute to excitotoxic injury during SE. Therapies that directly antagonize NMDA receptors may be a useful therapeutic strategy during refractory SE.

► NMDA receptor #'s increase at hippocampal synapses by 1 h of status epilepticus (SE). ► NMDA receptor (NMDAR) current increases imply more excitatory receptor activity in SE. ► Phasic & tonic current increases suggest more NMDAR at post- & extra-synaptic sites. ► The surface expression increase of NMDARs with SE is NR2B subunit-selective. ► NMDAR-mediated hyperactive networks may help sustain SE and cause excitotoxicity.