Inhibitory actions of the gamma-aminobutyric acid in pediatric Sturge-Weber syndrome.
OBJECTIVE
The mechanisms of epileptogenesis in Sturge-Weber syndrome (SWS) are unknown. We explored the properties of neurons from human pediatric SWS cortex in vitro and tested in particular whether gamma-aminobutyric acid (GABA) excites neurons in SWS cortex, as has been suggested for various types of epilepsies.


METHODS
Patch-clamp and field potential recordings and dynamic biphoton imaging were used to analyze cortical tissue samples obtained from four 6- to 14-month-old pediatric SWS patients during surgery.


RESULTS
Neurons in SWS cortex were characterized by a relatively depolarized resting membrane potential, as was estimated from cell-attached recordings of N-methyl-D-aspartate channels. Many cells spontaneously fired action potentials at a rate proportional to the level of neuronal depolarization. The reversal potential for GABA-activated currents, assessed by cell-attached single channel recordings, was close to the resting membrane potential. All spontaneously firing neurons recorded in cell-attached mode or imaged with biphoton microscopy were inhibited by GABA. Spontaneous epileptiform activity in the form of recurrent population bursts was suppressed by glutamate receptor antagonists, the GABA(A) receptor agonist isoguvacine, and the positive allosteric GABA(A) modulator diazepam. Blockade of GABA(A) receptors aggravated spontaneous epileptiform activity. The NKCC1 antagonist bumetanide had little effect on epileptiform activity.


CONCLUSIONS
SWS cortical neurons have a relatively depolarized resting membrane potential and spontaneously fire action potentials that may contribute to increased network excitability. In contrast to previous data depicting excitatory and proconvulsive actions of GABA in certain pediatric and adult epilepsies, GABA plays mainly an inhibitory and anticonvulsive role in SWS pediatric cortex.
Tyzio
Roman
R
INMED-INSERM U901, Marseille, Paris, France.
Khalilov
Ilgam
I
Represa
Alfonso
A
Crepel
Valerie
V
Zilberter
Yuri
Y
Rheims
Sylvain
S
Aniksztejn
Laurent
L
Cossart
Rosa
R
Nardou
Romain
R
Mukhtarov
Marat
M
Minlebaev
Marat
M
Epsztein
Jérôme
J
Milh
Mathieu
M
Becq
Helene
H
Jorquera
Isabel
I
Bulteau
Christine
C
Fohlen
Martine
M
Oliver
Viviana
V
Dulac
Olivier
O
Dorfmüller
Georg
G
Delalande
Olivier
O
Ben-Ari
Yehezkel
Y
Khazipov
Roustem
R
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D002034:Bumetanide / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D003975:Diazepam / Q000494:pharmacology; D004827:Epilepsy / Q000188:drug therapy / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007539:Isonicotinic Acids / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011963:Receptors, GABA-A / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology; D064506:Solute Carrier Family 12, Member 2; D013341:Sturge-Weber Syndrome / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D007539:Isonicotinic Acids; D011963:Receptors, GABA-A; D017470:Receptors, Glutamate; C578877:SLC12A2 protein, human; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D005680:gamma-Aminobutyric Acid; D003975:Diazepam; C015300:isoguvacine