Mechanisms of status epilepticus: -Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor hypothesis

Prolonged seizures of status epilepticus (SE) result from failure of mechanisms of seizure termination or activation of mechanisms that sustain seizures. Reduced -aminobutyric acid type A receptor-mediated synaptic transmission contributes to impairment of seizure termination. However, mechanisms that sustain prolonged seizures are not known. We propose that insertion of GluA1 subunits at the glutamatergic synapses causes potentiation of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR)-mediated neurotransmission, which helps to spread and sustain seizures. The AMPAR-mediated neurotransmission of CA1 pyramidal neurons was increased in animals in SE induced by pilocarpine. The surface membrane expression of GluA1 subunit-containing AMPARs on CA1 pyramidal neurons was also increased. Blockade of N-methyl-d-aspartate receptors 10minutes after the onset of continuous electrographic seizure activity prevented the increase in the surface expression of GluA1 subunits. N-methyl-d-aspartate receptor antagonist MK-801 in conjunction with diazepam also terminated seizures that were refractory to MK-801 or diazepam alone. Future studies using mice lacking the GluA1 subunit expression will provide further insights into the role of GluA1 subunit-containing AMPAR plasticity in sustaining seizures of SE.