Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus

Karthik Rajasekaran, Marko Todorovic, Jaideep Kapur

Research output: Contribution to journalArticle

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Abstract

Objective: A study was undertaken to characterize the plasticity of AMPA receptor (AMPAR)-mediated neurotransmission in the hippocampus during status epilepticus (SE). Methods: SE was induced by pilocarpine, and animals were studied 10 minutes (refractory SE) or 60 minutes (late SE) after the onset of the first grade 5 seizures. AMPAR-mediated currents were recorded from CA1 pyramidal neurons and dentate granule cells (DGCs) by voltage clamp technique. The surface expression of GluA2 subunit on hippocampal membranes was determined using a biotinylation assay. GluA2 internalization and changes in intracellular calcium ([Ca] i) levels were studied in hippocampal cultures using immunocytochemical and live-imaging techniques. AMPAR antagonist treatment of SE was evaluated by video and electroencephalography. Results: AMPAR-mediated currents recorded from CA1 neurons from refractory and late SE animals were inwardly rectifying, and philanthotoxin-sensitive; similar changes were observed in recordings obtained from DGCs from refractory SE animals. GluA2 subunit surface expression was reduced in the hippocampus during refractory and late SE. In cultured hippocampal pyramidal neurons, recurrent bursting diminished surface expression of the GluA2 subunit and enhanced its internalization rate. Recurrent bursting-induced increase in [Ca] i levels was reduced by selective inhibition of GluA2-lacking AMPARs. GYKI-52466 terminated diazepam-refractory SE. Interpretation: During SE, there is rapid, ongoing plasticity of AMPARs with the expression of GluA2-lacking AMPARs. These receptors provide another source of Ca 2+ entry into the principal neurons. Benzodiazepam-refractory SE can be terminated by AMPAR antagonism. The data identify AMPARs as a potential therapeutic target for the treatment of SE.

Original languageEnglish (US)
Pages (from-to)91-102
Number of pages12
JournalAnnals of Neurology
Volume72
Issue number1
DOIs
StatePublished - Jul 2012

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AMPA Receptors
Status Epilepticus
Rodentia
Calcium
Pyramidal Cells
Hippocampus
Biotinylation
Neurons
Pilocarpine
Patch-Clamp Techniques
Diazepam
Synaptic Transmission
Electroencephalography
Seizures

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

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Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. / Rajasekaran, Karthik; Todorovic, Marko; Kapur, Jaideep.

In: Annals of Neurology, Vol. 72, No. 1, 07.2012, p. 91-102.

Research output: Contribution to journalArticle

Rajasekaran, Karthik ; Todorovic, Marko ; Kapur, Jaideep. / Calcium-permeable AMPA receptors are expressed in a rodent model of status epilepticus. In: Annals of Neurology. 2012 ; Vol. 72, No. 1. pp. 91-102.
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