Developmental changes in GABAergic actions and seizure susceptibility in the rat hippocampus.
The immature brain is prone to seizures but the underlying mechanisms are poorly understood. We explored the hypothesis that increased seizure susceptibility during early development is due to the excitatory action of GABA. Using noninvasive extracellular field potential and cell-attached recordings in CA3 of Sprague-Dawley rat hippocampal slices, we compared the developmental alterations in three parameters: excitatory actions of GABA, presence of the immature pattern of giant depolarizing potentials (GDPs) and severity of epileptiform activity generated by high potassium. The GABA(A) receptor agonist isoguvacine increased firing of CA3 pyramidal cells in neonatal slices while inhibiting activity in adults. A switch in the GABA(A) signalling from excitation to inhibition occurred at postnatal day (P) 13.5 +/- 0.4. Field GDPs were present in the form of spontaneous population bursts until P12.7 +/- 0.3. High potassium (8.5 mm) induced seizure-like events (SLEs) in 35% of slices at P7-16 (peak at P11.3 +/- 0.4), but only interictal activity before and after that age. The GABA(A) receptor antagonist bicuculline reduced the frequency or completely blocked SLEs and induced interictal clonic-like activity accompanied by a reduction in the frequency but an increase in the amplitude of the population spikes. In slices with interictal activity, bicuculline typically caused a large amplitude interictal clonic-like activity at all ages; in slices from P5-16 rats it was often preceded by one SLE at the beginning of bicuculline application. These results suggest that, in the immature hippocampus, GABA exerts dual (both excitatory and inhibitory) actions and that the excitatory component in the action of GABA may contribute to increased excitability during early development.
Section of Neurology, Neuroscience Center at Dartmouth, Dartmouth Medical School, Lebanon, New Hampshire, 03756, USA. khazipov@inmed.univ-mrs.fr
Roustem
R
Khazipov
Ilgam
I
Khalilov
Roman
R
Tyzio
Elena
E
Morozova
Yezekiel
Y
Ben-Ari
Gregory L
GL
Holmes
D000375:Aging / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D004198:Disease Susceptibility / Q000503:physiopathology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D066298:In Vitro Techniques; D007539:Isonicotinic Acids / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects; D018408:Patch-Clamp Techniques / Q000379:methods; D011188:Potassium / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000254:growth & development*; D051381:Rats; D012640:Seizures / Q000503:physiopathology*; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018755:GABA Agonists; D018756:GABA Antagonists; D007539:Isonicotinic Acids; D005680:gamma-Aminobutyric Acid; D011188:Potassium; D001640:Bicuculline; C015300:isoguvacine