cgp-55845a and Seizures

The high-fat, low-carbohydrate ketogenic diet (KD) is an effective clinical treatment for epilepsy in juveniles, especially for drug-resistant seizures. The KD results in elevated production of ketone bodies (KB's), such as beta-hydroxybutyrate (β-HB), which are thought to have anticonvulsant properties; however, their exact mechanism of action is unknown. In vitro, KB effects on reducing neuronal firing rates are mediated in part by K

Topics: 3-Hydroxybutyric Acid; Animals; Animals, Genetically Modified; Anticonvulsants; Disease Models, Animal; Drosophila melanogaster; Drosophila Proteins; GABA Antagonists; Hypoglycemic Agents; KATP Channels; Phosphinic Acids; Propanolamines; Receptors, GABA-B; Seizures; Signal Transduction; Statistics, Nonparametric; Tolbutamide

We obtained field, K(+) selective and "sharp" intracellular recordings from the rat entorhinal (EC) and perirhinal (PC) cortices in an in vitro brain slice preparation to identify the events occurring at interictal-to-ictal transition during 4-aminopyridine application. Field recordings revealed interictal- (duration: 1.1 to 2.2s) and ictal-like (duration: 31 to 103s) activity occurring synchronously in EC and PC; in addition, interictal spiking in PC increased in frequency shortly before the onset of ictal oscillatory activity thus resembling the hypersynchronous seizure onset seen in epileptic patients and in in vivo animal models. Intracellular recordings with K-acetate+QX314-filled pipettes in PC principal cells showed that spikes at ictal onset had post-burst hyperpolarizations (presumably mediated by postsynaptic GABAA receptors), which gradually decreased in amplitude. This trend was associated with a progressive positive shift of the post-burst hyperpolarization reversal potential. Finally, the transient elevations in [K(+)]o (up to 4.4mM from a base line of 3.2mM) - which occurred with the interictal events in PC - progressively increased (up to 7.3mM) with the spike immediately preceding ictal onset. Our findings indicate that hypersynchronous seizure onset in rat PC is caused by dynamic weakening of GABAA receptor signaling presumably resulting from [K(+)]o accumulation.

Topics: 4-Aminopyridine; 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Animals; Cations, Monovalent; Cerebral Cortex; Excitatory Amino Acid Antagonists; GABA Antagonists; Neurons; Periodicity; Phosphinic Acids; Picrotoxin; Piperazines; Potassium; Propanolamines; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, GABA-B; Receptors, N-Methyl-D-Aspartate; Seizures; Tissue Culture Techniques

GABA, which generally mediates inhibitory synaptic transmissions, occasionally acts as an excitatory transmitter through intense GABA(A) receptor activation even in adult animals. The excitatory effect results from alterations in the gradients of chloride, bicarbonate, and potassium ions, but its functional role still remains a mystery. Here we show that such GABAergic excitation participates in the expression of seizure-like rhythmic synchronization (afterdischarge) in the mature hippocampal CA1 region. Seizure-like afterdischarge was induced by high-frequency synaptic stimulation in the rat hippocampal CA1-isolated slice preparations. The hippocampal afterdischarge was completely blocked by selective antagonists of ionotropic glutamate receptors or of GABA(A) receptor, and also by gap-junction inhibitors. In the CA1 pyramidal cells, oscillatory depolarizing responses during the afterdischarge were largely dependent on chloride conductance, and their reversal potentials (average -38 mV) were very close to those of exogenously applied GABAergic responses. Moreover, intracellular loading of the GABA(A) receptor blocker fluoride abolished the oscillatory responses in the pyramidal cells. Finally, the GABAergic excitation-driven afterdischarge has not been inducible until the second postnatal week. Thus, excitatory GABAergic transmission seems to play an active functional role in the generation of adult hippocampal afterdischarge, in cooperation with glutamatergic transmissions and possible gap junctional communications. Our findings may elucidate the cellular mechanism of neuronal synchronization during seizure activity in temporal lobe epilepsy.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Acetazolamide; Animals; Animals, Newborn; Anti-Ulcer Agents; Atropine; Bicuculline; Carbenoxolone; Carbonic Anhydrase Inhibitors; Chlorides; Drug Interactions; Electric Conductivity; Electric Stimulation; Evoked Potentials; Excitatory Amino Acid Antagonists; Fluorides; GABA Antagonists; gamma-Aminobutyric Acid; Hippocampus; In Vitro Techniques; Membrane Potentials; Muscarinic Antagonists; Patch-Clamp Techniques; Phosphinic Acids; Propanolamines; Pyramidal Cells; Rats; Rats, Wistar; Seizures; Valine