Molecular basis for the GABAA receptor-mediated tonic inhibition in rat somatosensory cortex

Cereb Cortex. 2007 Aug;17(8):1782-7. doi: 10.1093/cercor/bhl087. Epub 2006 Sep 22.

Abstract

Fast inhibitory synaptic transmission is primarily mediated by synaptically released gamma-aminobutyric acid (GABA) acting on postsynaptic GABA(A) receptors. GABA acting on GABA(A) receptors produces not only phasic but also tonic inhibitions by persistent activation of extrasynaptic receptors. However, the mechanistic characteristics of tonic inhibition in the neocortex are not well-understood. To address this, we studied pharmacologically isolated GABA(A) receptor-mediated currents in neocortical pyramidal neurons in rat brain slices. Bath application of bicuculline blocked miniature inhibitory postsynaptic currents (mIPSCs) and produced an outward shift in baseline holding current (I(hold)). Low concentrations of SR95531, a competitive GABA(A) receptor antagonist, abolished mIPSCs but had no significant effect on I(hold). The benzodiazepine midazolam produced an inward shift in I(hold) by augmenting tonic GABA(A) receptor-mediated currents, which were significantly greater in layer V neurons than in layer II/III. Single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a relatively higher expressions of alpha1 and alpha5 subunit mRNA in layer V neurons. L-655708, an alpha5 subunit-specific inverse agonist, reduced tonic currents in layer V but not in layer II/III neurons, whereas zolpidem, an alpha1-subunit agonist, exerted equivalent effects in both layers. These data suggest that the alpha1 GABA(A) receptor subunit is generally involved in tonic inhibition in pyramidal neurons of the neocortex, whereas the alpha5 subunit is specifically involved in layer V neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 6-Cyano-7-nitroquinoxaline-2,3-dione / pharmacology
  • Animals
  • Benzodiazepines / pharmacology
  • Desoxycorticosterone / analogs & derivatives
  • Desoxycorticosterone / pharmacology
  • GABA Agonists / pharmacology
  • GABA Modulators / pharmacology
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Midazolam / pharmacology
  • Neocortex / physiology
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • Pyridines / pharmacology
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Wistar
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Somatosensory Cortex / cytology
  • Somatosensory Cortex / drug effects
  • Somatosensory Cortex / physiology*
  • Zolpidem

Substances

  • GABA Agonists
  • GABA Modulators
  • Imidazoles
  • L 655,708
  • Pyridines
  • RNA, Messenger
  • Receptors, GABA-A
  • Benzodiazepines
  • Desoxycorticosterone
  • tetrahydrodeoxycorticosterone
  • 6-Cyano-7-nitroquinoxaline-2,3-dione
  • Zolpidem
  • Midazolam