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Bicuculline‐ and neurosteroid‐sensitive tonic chloride current in rat hypoglossal motoneurons and atypical dual effect of SR 95531
Author(s) -
ChesnoyMarchais Dominique
Publication year - 2013
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.12074
Subject(s) - bicuculline , chemistry , gabaa receptor , inhibitory postsynaptic potential , neuroactive steroid , pharmacology , gaba receptor antagonist , allopregnanolone , neuroscience , biophysics , receptor , biochemistry , biology
Hypoglossal motoneurons ( HM s) 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 GABA A antagonists picrotoxin ( PTX ) and 2‐(3‐carboxypropyl)‐3‐amino‐6‐(4 methoxyphenyl)pyridazinium bromide) ( SR 95531; gabazine), but persisted in the presence of a specific blocker of α5‐containing GABA A receptors. Addition of 2 μ m 4,5,6,7‐tetrahydroisoxazolo[5,4‐ c ]pyridin‐3‐ol hydrochloride ( THIP ), known to preferentially activate GABA A receptors devoid of a γ‐subunit, induced a sustained anionic current that could be further enhanced by neurosteroids such as allopregnanolone (100 n m ). Thus, HM s show a tonic inhibitory current carried by extrasynaptic γ‐free GABA A receptors, highly sensitive to neurosteroids. A second result was obtained by using SR 95531 at concentrations sufficiently high to rapidly block the tonic current above the chloride equilibrium potential ( E C l ). Surprisingly, below E C l , SR 95531 (10–40 μ m ) activated a sustained inward current, associated with a conductance increase, and resistant to bicuculline or PTX (100 μ m ). Similarly, after blockade of the bicuculline‐sensitive current, SR 95531 activated an outward current above E C l . The bicuculline‐resistant anionic current activated by SR 95531 could be blocked by a GABA C receptor antagonist. Thus, two types of inhibitory GABA receptors, belonging to the GABA A and GABA C families, are able to show a sustained activity in HM s and provide promising targets for neuroprotection under overexcitatory situations known to easily damage these particularly fragile neurons.