Epileptiform discharge induced by 4-aminopyridine in magnesium-free medium in neocortical neurons: physiological and pharmacological characterization.
An in vitro model of epileptiform activity was developed to study the role of excitatory and inhibitory neurotransmitters in the epileptogenesis. Intracellular recordings were obtained from rat neocortical slices exposed to 4-aminopyridine in a magnesium-free solution. Spontaneous epileptiform activity consisting of paroxysmal depolarization shifts with associated spontaneous depolarizing postsynaptic potentials were observed. The paroxysmal depolarization shifts were blocked either by D,L-2-amino-5-phosphonovalerate (50 microM), an N-methyl-D-aspartate receptor antagonist, or by 6-cyano-7-nitroquinoxaline-2.3-dione (10 microM), a non-N-methyl-D-aspartate receptor antagonist. These glutamate receptor antagonists also reduced the occurrence of spontaneous depolarizing postsynaptic potentials. Bicuculline methiodide, an antagonist of GABAA receptors, suppressed spontaneous depolarizing postsynaptic potentials, while it reduced the frequency of paroxysmal depolarization shifts and increased their duration. Hyperpolarization of the membrane potential by continuous current injection increased the frequency of paroxysmal depolarization shifts and reduced their duration, but it reduced the occurrence of spontaneous postsynaptic potentials. Paroxysmal depolarization shifts were blocked by tetrodotoxin (1 microM). The duration and the frequency of paroxysmal depolarization shift were reduced by dopamine (30-300 microM) in a dose-dependent manner. Our model suggests a different involvement of excitatory and inhibitory processes in the generation of epileptiform activity.
Siniscalchi
A
A
IRCCS Ospedale S. Lucia, Rome, Italy.
Calabresi
P
P
Mercuri
N B
NB
Bernardi
G
G
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D015761:4-Aminopyridine; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D003712:Dendrites / Q000737:chemistry / Q000187:drug effects; D004298:Dopamine / Q000494:pharmacology; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D008274:Magnesium / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D019579:Neocortex / Q000166:cytology / Q000503:physiopathology*; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000502:physiology; D017729:Presynaptic Terminals / Q000737:chemistry / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D003470:Culture Media; D018691:Excitatory Amino Acid Antagonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D015761:4-Aminopyridine; D008274:Magnesium; D004298:Dopamine