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Keywords:

  • allopregnanolone;
  • GABA receptors;
  • gabazine;
  • THIP (gaboxadol);
  • tonic inhibition;
  • TPMPA

Abstract

Hypoglossal motoneurons (HMs) are known to be under ‘permanent’ bicuculline-sensitive inhibition and to show ‘transient’ synaptic γ-aminobutyric acid (GABA)A and glycine inhibitory responses. The present paper describes a permanent bicuculline-sensitive current that should contribute to their tonic inhibition. This current was recorded in brainstem slices superfused without any exogenous agonist and remained detectable with tetrodotoxin. It could also be blocked by the other GABAA antagonists picrotoxin (PTX) and 2-(3-carboxypropyl)-3-amino-6-(4 methoxyphenyl)pyridazinium bromide) (SR95531; gabazine), but persisted in the presence of a specific blocker of α5-containing GABAA receptors. Addition of 2 μm 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrochloride (THIP), known to preferentially activate GABAA receptors devoid of a γ-subunit, induced a sustained anionic current that could be further enhanced by neurosteroids such as allopregnanolone (100 nm). Thus, HMs show a tonic inhibitory current carried by extrasynaptic γ-free GABAA receptors, highly sensitive to neurosteroids. A second result was obtained by using SR95531 at concentrations sufficiently high to rapidly block the tonic current above the chloride equilibrium potential (ECl). Surprisingly, below ECl, SR95531 (10–40 μm) activated a sustained inward current, associated with a conductance increase, and resistant to bicuculline or PTX (100 μm). Similarly, after blockade of the bicuculline-sensitive current, SR95531 activated an outward current above ECl. The bicuculline-resistant anionic current activated by SR95531 could be blocked by a GABAC receptor antagonist. Thus, two types of inhibitory GABA receptors, belonging to the GABAA and GABAC families, are able to show a sustained activity in HMs and provide promising targets for neuroprotection under overexcitatory situations known to easily damage these particularly fragile neurons.