Masking synchronous GABA-mediated potentials controls limbic seizures.
OBJECTIVE
We determined how CA3-driven interictal discharges block ictal activity generated in the entorhinal cortex during bath application of 4-aminopyridine (4AP, 50 microM).


METHODS
Field potential and [K+]o recordings were obtained from mouse combined hippocampus-entorhinal cortex slices maintained in vitro.


RESULTS
4AP induced N-methyl-d-aspartate (NMDA) receptor-dependent ictal discharges that originated in the entorhinal cortex, disappeared over time, but were reestablished by cutting the Schaffer collateral (n = 20) or by depressing CA3 network excitability with local application of glutamatergic receptor antagonists (n = 5). In addition, two types of interictal activity occurred throughout the experiment. The first type was CA3 driven and was abolished by a non-NMDA glutamatergic receptor antagonist. The second type was largely contributed by gamma-aminobutyric acid type A (GABAA) receptor-mediated conductances and persisted during blockade of glutamatergic transmission. The absence of CA3-driven interictal discharges in the entorhinal cortex after Schaffer collateral cut facilitated the GABA-mediated interictal potentials that corresponded to large [K+]o elevations and played a role in ictal discharge initiation. Accordingly, ictal discharges along with GABA-mediated interictal potentials disappeared during GABAA-receptor blockade (n = 7) or activation of mu-opioid receptors that inhibit GABA release (n = 4).


CONCLUSIONS
Our findings suggest that CA3-driven interictal events restrain ictal discharge generation in the entorhinal cortex by modulating the size of interictal GABA-mediated potentials that lead to large [K+]o elevations capable of initiating ictal discharges in this structure.
Barbarosie
Michaela
M
Montreal Neurological Institute and Department of Neurology, McGill University, Montreal, Quebec, Canada.
Louvel
Jacques
J
D'Antuono
Margherita
M
Kurcewicz
Irène
I
Avoli
Massimo
M
D015761:4-Aminopyridine / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D046508:Culture Techniques; D004569:Electroencephalography / Q000187:drug effects*; D018728:Entorhinal Cortex / Q000187:drug effects* / Q000503:physiopathology; D004828:Epilepsies, Partial / Q000139:chemically induced / Q000503:physiopathology*; D007736:Kynurenic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009415:Nerve Net / Q000187:drug effects / Q000503:physiopathology*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D015221:Potassium Channels; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015761:4-Aminopyridine; D007736:Kynurenic Acid