title: Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus.
abstract: 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 α-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 AMPA-evoked excitatory currents recorded from the CA1 pyramidal neurons were larger than those recorded in the controls. The evoked EPSCs rectified inwardly. In these animals, the surface expression of GluA1 subunit-containing AMPARs was increased in the CA1 pyramidal neurons. The phosphorylation of the GluA1 subunit on S831 and S845 residues was reduced in animals in SE. In contrast, the GluA1 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 GluA1 subunits. NMDAR blockade also prevented the dephosphorylation of the S845 residue but not that of S831. Targeting NMDARs and AMPARs may provide novel strategies to treat benzodiazepine-refractory SE.
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, United States.
authors.forename: Suchitra
authors.initials: S
authors.lastname: Joshi
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, United States.
authors.forename: Karthik
authors.initials: K
authors.lastname: Rajasekaran
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, United States.
authors.forename: Huayu
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, United States.
authors.forename: John
authors.initials: J
authors.lastname: Williamson
authors.affiliation: Department of Neurology, University of Virginia, Charlottesville, VA 22908, United States; Department of Neuroscience University of Virginia, Charlottesville, VA 22908, United States. Electronic address: jk8t@virginia.edu.
authors.forename: Jaideep
authors.initials: J
authors.lastname: Kapur
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000502:physiology*; D013226:Status Epilepticus / Q000188:drug therapy / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA
keywords: AMPA receptor; Benzodiazepines; GluA1 subunit phosphorylation; MK-801; Status epilepticus; mEPSCs