EPILEPTIC FOCUS INDUCED IN RAT BY INTRAHIPPOCAMPAL CHOLERA-TOXIN - NEURONAL PROPERTIES IN-VITRO

Injecting 0.5-1.0 mug of cholera toxin into rat hippocampus induces a chronic epileptic focus which generates interictal discharges and brie f epileptic seizures intermittently over the following seven to 10 day s. Here we examined the electrophysiological properties of hippocampal slices prepared from these rats three to four days after injection, a t the height of the epileptic syndrome. These slices generated epilept ic discharges in response to electrical stimulation of afferent pathwa ys. In many cases epileptic discharges occurred spontaneously in the C A3 subregion; these usually lasted < 200 ms, but they could last < 0.6 s. Intracellular recordings from pyramidal layer cells revealed depol arization shifts synchronous with the epileptic field potentials. Thes e depolarization shifts had slow onsets compared with those induced by blocking inhibition with bicuculline (depolarizations started a mean of 57 ms before, and reached 5.2 mV by, the onset of the cholera toxin epileptic field potential, compared with 12 ms and 3.6 mV respectivel y for 70 muM bicuculline methiodide). Extracellular unit recordings sh owed that the slow predepolarization seen in the cholera toxin focus w as associated with an acceleration of the firing of other pyramidal la yer neurons. The epileptic activity in this model cannot be attributed to the loss of synaptic inhibition, because inhibitory postsynaptic p otentials could be evoked when the synchronous bursts were blocked by increasing [Ca2+]o from 2 to 8 mM. Observations of monosynaptic inhibi tory postsynaptic currents isolated by application of 20 muM 6-cyano-7 -nitroquinoxaline-2,3-dione, 50 muM DL-2-amino-5-phosphonovaleric acid and 100-200 muM amino-2-(4-chlorophenyl)-2-hydroxy-propylsulphonic ac id showed a small effect of the toxin only on the time course of the i nhibitory postsynaptic current. On the other hand, there were signific ant changes in the intrinsic properties of individual neurons. The mem brane potentials of cells in the cholera toxin focus did not differ fr om those in slices from rats injected with vehicle solution, but their input resistances were significantly increased. Unlike the other cell ular changes in this model, the increase in input resistance was not s een in slices exposed acutely to 1 mug/ml cholera toxin for 30 min, su ggesting there may be morphological changes in the chronic focus. Acti on potential accommodation and the slow afterhyperpolarization were de pressed in both acute and chronic epileptic tissue, indicating impairm ents of Ca2+- and/or voltage-dependent K+ currents, and we conclude th at these provide the most likely basis for cholera toxin epileptogenes is.