Intrinsic activation of GABA(A) receptors suppresses epileptiform activity in the cerebral cortex of immature mice.

Abstract

PURPOSE:

Activation of ionotropic γ-aminobutyric acid type A (GABA(A) ) receptors induces in immature neocortical neurons a membrane depolarization that may contribute to the higher epilepsy susceptibility in newborns. To elucidate whether depolarizing GABAergic responses enhance or attenuate epileptiform activity in the immature neocortex, we investigated the effect of agonists, antagonists, and positive modulators of GABA(A) receptors on epileptiform activity.

METHODS:

We performed in vitro field potential recordings on isolated whole neocortex preparations and whole cell recordings of identified pyramidal neurons in 400-μm slices of immature (postnatal day 1-7) mice. Epileptiform activity was induced by low Mg²(+) solutions with or without 50-100 μm 4-aminopyridine.

RESULTS:

  Bath application of GABA (3-100 μm, in the presence of tiagabine) attenuated epileptiform activity. The GABA transporter isoform 1 (GAT-1) inhibitor tiagabine (30 μm) and the GAT-2/3 specific inhibitor SNAP 5114 (40 μm) reduced the frequency of epileptiform activity. The benzodiazepines midazolam (0.2 μm) and zolpidem (0.5 μm) as well as the barbiturate phenobarbital (30 μm) slightly attenuated epileptiform activity. Continuous bath application of the GABAergic antagonist gabazine (SR-95531, 2-3 μm) or picrotoxin (15 μm) induced epileptiform discharges.

DISCUSSION:

These results demonstrate, that (1) the activation or positive modulation of GABA(A) receptors attenuates epileptiform activity, (2) GABA(A) antagonists mediate a disinhibition, and (3) GABA uptake contributes to the regulation of extracellular GABA in immature neocortex. We conclude from these findings that a constant inhibition via GABA(A) receptors is required to suppress epileptiform activity already in the immature neocortex.

• Authors: Daniel Richter, Heiko J Luhmann, Werner Kilb
• Journal: Epilepsia (Epilepsia) Vol. 51 Issue 8 Pg. 1483-92 (Aug 2010) ISSN: 1528-1167 [Electronic] United States
• PMID: 20491873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Wiley Periodicals, Inc. © 2010 International League Against Epilepsy.

Chemical References

• 1-(2-(tris(4-methoxyphenyl)methoxy)ethyl)-3-piperidinecarboxylic acid
• Anisoles
• Enzyme Inhibitors
• Excitatory Amino Acid Antagonists
• GABA Agonists
• GABA Antagonists
• Nipecotic Acids
• Potassium Channel Blockers
• Pyridazines
• Receptors, GABA-A
• gamma-Aminobutyric Acid
• 6-Cyano-7-nitroquinoxaline-2,3-dione
• gabazine
• 4-Aminopyridine
• Magnesium
• Tiagabine

Topics

• 4-Aminopyridine (pharmacology)
• 6-Cyano-7-nitroquinoxaline-2,3-dione (pharmacology)
• Action Potentials (drug effects, physiology)
• Animals
• Animals, Newborn
• Anisoles (pharmacology)
• Cerebral Cortex (drug effects, growth & development, metabolism)
• Dose-Response Relationship, Drug
• Drug Interactions
• Enzyme Inhibitors (pharmacology)
• Excitatory Amino Acid Antagonists (pharmacology)
• GABA Agonists (pharmacology)
• GABA Antagonists (pharmacology)
• Gene Expression Regulation (drug effects, physiology)
• In Vitro Techniques
• Magnesium (metabolism)
• Mice
• Mice, Inbred C57BL
• Nipecotic Acids (pharmacology)
• Patch-Clamp Techniques (methods)
• Potassium Channel Blockers (pharmacology)
• Pyridazines (pharmacology)
• Receptors, GABA-A (metabolism)
• Tiagabine
• gamma-Aminobutyric Acid (metabolism, pharmacology)