Age-dependent Modulation of Hippocampal Excitability by KCNQ-channels

Epilepsy Res. 2003 Feb;53(1-2):81-94. doi: 10.1016/s0920-1211(02)00249-8.

Abstract

Recently, mutations of KCNQ2 or KCNQ3, members of the KCNQ-related K(+)-channel (KCNQ-channel) family, were identified as cause of benign familial neonatal convulsions (BFNC). However, the exact pathogenic mechanisms of age-dependent development and spontaneous remission of BFNC remain to be elucidated. To clarify the age-dependent etiology of BFNC, we determined age-dependent functional switching of KCNQ-channels, GABAergic- and glutamatergic-transmission in rat hippocampus. The effects of inhibitors of KCNQ-channel, GABA- and glutamate-receptors on propagation of neuronal-excitability and neurotransmitter release were determined by 64-channel multielectrode-dish (MED64), whole-cell recording, in vitro release technique and in vivo microdialysis biosensor, using rat hippocampus from day of birth (P0) to postnatal-day 56 (P56). Inhibition of KCNQ-channels enhanced depolarization-induced glutamate and GABA releases during P0-P7, but not during P14-P28. Inhibition of KCNQ-channels magnified neuronal-excitability propagation from P0 to P14: maximal at P3, but this effect disappeared by P28. GABA(A)-receptor inhibition surprisingly reduced neuronal-excitability propagation during P0-P3, but not at P7. AMPA/glutamate-receptors inhibition reduced propagation of neuronal-excitability throughout the study period. KCNQ-channels inhibition shortened spike-frequency adaptation, but this stimulation was more predominant during P<7 than P>14. During the first week of life, KCNQ-channels performed as a predominant inhibitory system, whereas after this period GABAergic-transmission switched from excitatory to inhibitory function. Contrary, glutamatergic-transmission has acquired as excitatory function from P0. These findings suggest that the pathogenic mechanisms of age-dependent development and spontaneous remission of BFNC are, at least partially, associated with the interaction between age-dependent reduction of inhibitory KCNQ-channel activity and age-dependent functional switching of the GABAergic-system from excitatory to inhibitory action in neonatal CNS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology*
  • Animals
  • Biosensing Techniques
  • Cortical Spreading Depression / physiology
  • Epilepsy, Benign Neonatal / genetics*
  • Glutamic Acid / physiology
  • Hippocampus / physiology*
  • Male
  • Membrane Potentials / physiology
  • Microdialysis
  • Neurons / drug effects
  • Neurons / physiology
  • Neurotransmitter Agents / metabolism
  • Potassium / pharmacology
  • Potassium Channels / deficiency
  • Potassium Channels / genetics
  • Potassium Channels / physiology*
  • Rats
  • Rats, Wistar
  • Remission, Spontaneous
  • Synaptic Transmission
  • gamma-Aminobutyric Acid / physiology

Substances

  • Neurotransmitter Agents
  • Potassium Channels
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Potassium