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2‐Deoxy‐ d ‐glucose enhances tonic inhibition through the neurosteroid‐mediated activation of extrasynaptic GABA A receptors
Author(s) -
Forte Nicola,
Medrihan Lucian,
Cappetti Beatrice,
Baldelli Pietro,
Benfenati Fabio
Publication year - 2016
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13578
Subject(s) - gabaergic , tonic (physiology) , bicuculline , chemistry , gabaa receptor , hippocampal formation , neuroactive steroid , neuroscience , gaba receptor antagonist , receptor , pharmacology , biochemistry , biology
Summary Objective The inhibition of glycolysis exerts potent antiseizure effects, as demonstrated by the efficacy of ketogenic and low‐glucose/nonketogenic diets in the treatment of drug‐resistant epilepsy. ATP ‐sensitive potassium (K ATP ) channels have been initially identified as the main determinant of the reduction of neuronal hyperexcitability. However, a plethora of other mechanisms have been proposed. Herein, we report the ability of 2‐deoxy‐ d ‐glucose (2‐ DG ), a glucose analog that inhibits glycolytic enzymes, of potentiating γ‐aminobutyric acid ( GABA )ergic tonic inhibition via neurosteroid‐mediated activation of extrasynaptic GABA A receptors. Methods Acute effects of 2‐ DG on the ATP ‐sensitive potassium currents, GABA ergic tonic inhibition, firing activity, and interictal events were assessed in hippocampal slices by whole‐cell patch‐clamp and local field potential recordings of dentate gyrus granule cells. Results Acute application of 2‐ DG activates two distinct outward conductances: a K ATP channel–mediated current and a bicuculline‐sensitive tonic current. The effect of 2‐ DG on such GABA ergic tonic currents was fully prevented by either finasteride or PK 11195, which are specific inhibitors of the neurosteroidogenesis pathway acting via different mechanisms. Moreover, the oxidized form of vitamin C, dehydroascorbic acid, known for its ability to induce neurosteroidogenesis, also activated a bicuculline‐sensitive tonic current in a manner indistinguishable from that of 2‐ DG . Finally, we found that the enhancement of K ATP current by 2‐ DG primarily regulates intrinsic firing rate of granule cells, whereas the increase of the GABA ergic tonic current plays a key role in reducing the frequency of interictal events evoked by treatment of hippocampal slices with the convulsive agent 4‐aminopyridine. Significance We demonstrated, for the first time, that 2‐ DG potentiates the extrasynaptic tonic GABA ergic current through activation of neurosteroidogenesis. Such tonic inhibition represents the main conductance responsible for the antiseizure action of this glycolytic inhibitor.