Glutamate receptor antagonists and benzodiazepine inhibit the progression of granule cell dispersion in a mouse model of mesial temporal lobe epilepsy

Epilepsia. 2005 Feb;46(2):193-202. doi: 10.1111/j.0013-9580.2005.35504.x.


Purpose: Unilateral intrahippocampal injection of kainic acid (KA) in adult mice induces the progressive dispersion of dentate granule cells, one of the characteristic pathologic changes of mesial temporal lobe epilepsy. However, little is known about the mechanisms that trigger this dispersion. In this study, the possible involvement of glutamatergic and gamma-aminobutyric acid (GABA)ergic neurotransmissions in the development of granule cell dispersion (GCD) was examined in this model.

Methods: Antagonists of N-methyl-d-aspartate (NMDA) receptor (MK-801) and non-NMDA receptor (GYKI52466), and an agonist of benzodiazepine-GABA(A) receptor (midazolam) were injected before and after KA in various ways, and the morphologic changes of the hippocampus, especially GCD, were examined.

Results: MK-801 (5 mg/kg, i.p.) did not reduce GCD when injected 2 h before KA injection but inhibited GCD almost completely for <or=14 days, when injected 4 h after KA. However, mild to moderate dispersion was observed at 28 days, indicating that MK-801 may delay the progression of GCD. Similarly, daily treatment with MK-801 (2 x 1 mg/kg i.p./day) for the first 26 days after KA significantly reduced GCD. In contrast, GYKI52466 (30 mg/kg, s.c.) was effective only when it was injected before KA. A significant reduction of GCD was also observed after continuous administration of midazolam (10 mg/kg/h) after KA.

Conclusions: These data show that GCD in this mouse model is triggered by either the stimulation of the NMDA receptor or reduction of GABA(A)-mediated inhibition after intrahippocampal injection of KA. It is suggested that the increased excitation or the reduced inhibition or both could be one of the factors triggering or maintaining or both the process of GCD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzodiazepines / pharmacology*
  • Cell Count
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / pathology
  • Disease Models, Animal
  • Dizocilpine Maleate / pharmacology
  • Epilepsy, Temporal Lobe / chemically induced
  • Epilepsy, Temporal Lobe / pathology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • GABA Modulators / pharmacology
  • Hippocampus / drug effects*
  • Hippocampus / pathology
  • Kainic Acid / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Midazolam / pharmacology
  • Mossy Fibers, Hippocampal / drug effects
  • Mossy Fibers, Hippocampal / pathology
  • Neurons / drug effects
  • Neurons / pathology
  • Receptors, AMPA / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / drug effects


  • Excitatory Amino Acid Antagonists
  • GABA Modulators
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • GYKI 52466
  • Benzodiazepines
  • Dizocilpine Maleate
  • Midazolam
  • Kainic Acid