Epileptic focus induced by intrahippocampal cholera toxin in rat: time course and properties in vivo and in vitro.
A small dose (0.5-1.0 micrograms) of cholera toxin injected into rat hippocampus induced an epileptic focus which discharged intermittently for 7-10 days. Epileptic discharges lasting from 70 ms to 2 min were recorded in vivo through implanted electrodes. The longer bursts could generalize to the neocortex, and occasionally caused motor seizures. The epileptic bursts reached a maximum 3-4 days after injection, and then declined to occasional brief interictal discharges by 9 days. Postmortem histology revealed no evidence of gross pathology or neuronal loss. Hippocampal slices prepared from rats < 8 days after injection of cholera toxin, and maintained in vitro, generated brief spontaneous and evoked epileptic bursts, usually lasting < 1 s. Spontaneous bursts always started in subregion CA3c, and propagated through the pyramidal layer at a mean of 0.18 m/s. Intracellular recordings from CA3 pyramidal layer cells always revealed simultaneous paroxysmal depolarization shifts during epileptic bursts. Epileptic activity, both in vivo and in vitro, required the whole toxin molecule. Injections of either the B subunit or the vehicle solution were not epileptogenic. Therefore binding of the toxin to neuronal membranes, which is mediated by the B subunit, was not sufficient for the epileptogenic effects of cholera toxin. This suggested that the activation of Gs which requires the whole molecule, was necessary. Gs activation is known to stimulate cyclic AMP production, but forskolin, which directly stimulates adenyl cyclase, failed to produce epileptic activity, even though it depressed action potential accommodation and afterhyperpolarizations (AHPs). While further work is required to resolve the basic mechanisms of cholera toxin induced epileptic foci, we propose that they require the activation of Gs, which can enhance Ca2+ currents and modify excitatory synaptic transmission directly. Cyclic AMP induced changes in these properties cannot be excluded. However, cyclic AMP induced reductions in action potential accommodation and AHPs, which are found in cholera toxin foci, may contribute to, but are not sufficient for, epileptogenesis. Cholera toxin differs from the commonly used epileptic agents in that its main action is on G proteins and second messenger systems, rather than on synaptic transmission directly. Furthermore it has a prolonged time course, and does not cause gross pathology. These features combine to make it a distinctive model for epilepsy and neuronal synchronization.
Williams
S F
SF
Department of Physiology and Biophysics, St. Mary's Hospital Medical School, Imperial College, University of London, UK.
Colling
S B
SB
Whittington
M A
MA
Jefferys
J G
JG
D000818:Animals; D002772:Cholera Toxin / Q000008:administration & dosage / Q000633:toxicity*; D004828:Epilepsies, Partial / Q000139:chemically induced / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials; D008845:Microinjections; D009474:Neurons / Q000502:physiology; D011712:Pyramidal Tracts / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D002772:Cholera Toxin