Repeated application of 4-aminopyridine provoke an increase in entorhinal cortex excitability and rearrange AMPA and kainate receptors

Neurotox Res. 2015 May;27(4):441-52. doi: 10.1007/s12640-014-9515-7. Epub 2015 Jan 10.

Abstract

Entorhinal cortex is a highly epilepsy-prone brain region. Effects of repetitive seizures on ionotropic glutamate receptors (iGluRs) were investigated in rat entorhinal cortex slices. Seizures were induced by daily administration of 4-aminopyridine (4-AP). Electrophysiological, pharmacological and histological investigations were carried out to determine changes in synaptic efficacy and in sensitivity of iGluRs due to recurring seizures. Repeated 4-AP-induced seizures increased the amplitude of evoked synaptic field responses in rat entorhinal cortical slices. While vulnerability to inhibition of AMPA receptors by the specific antagonist GYKI 52466 was slightly reduced, responsiveness to NMDA receptor antagonist APV remained unaffected. Testing of bivalent cation permeability of iGluRs revealed reduced Ca(2+)-influx through non-NMDA receptors. According to the semi-quantitative histoblot analysis GluA1-4, GluA1, GluA2, GluK5, GluN1 and GluN2A subunit protein expression differently altered. While there was a marked decrease in the level of GluA1-4, GluA2 and GluK5 receptor subunits, GluA1 and GluN2A protein levels moderately increased. The results indicate that brief convulsions, repeated daily for 10 days can increase overall entorhinal cortex excitability despite a reduction in AMPA/kainate receptor activity, probably through the alteration of local network susceptibility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • 4-Aminopyridine / toxicity*
  • Animals
  • Benzodiazepines / pharmacology
  • Entorhinal Cortex / drug effects
  • Entorhinal Cortex / physiopathology*
  • Excitatory Amino Acid Agonists / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Kainic Acid / pharmacology
  • Male
  • Protein Subunits / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, AMPA / metabolism*
  • Receptors, Kainic Acid / agonists
  • Receptors, Kainic Acid / metabolism*
  • Seizures / chemically induced
  • Seizures / metabolism
  • Seizures / physiopathology*

Substances

  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Protein Subunits
  • Receptors, AMPA
  • Receptors, Kainic Acid
  • GYKI 52466
  • Benzodiazepines
  • 2-Amino-5-phosphonovalerate
  • 4-Aminopyridine
  • Kainic Acid