Dissociation of mossy fiber sprouting and electrically-induced seizure sensitivity: rapid kindling versus adaptation

It has been shown that massed stimulation (MS) of the amygdala or hippocamp us does not result in seizure progression but in the 'phenomenon of adaptat ion', whereas alternate day rapid kindling (ADRK) produces reliable kindlin g (Lothman, E.W., Williamson, J.M., 1994. Brain Res. 649, 71-84). The goal of the present experiment was to determine if the two different effects are due to differences in mossy fiber sprouting and/or different seizure and p ostictal spike propagation patterns. Nine rats underwent MS (66-70 stimulat ions separated by 5-min interstimulus interval), six were exposed to ADRK ( 12 stimulations/day, every 30 min, with 4 stimulus days, each separated by 1 stimulus-free day), five rats served as control. All rats had electrodes implanted bilaterally in dorsal and ventral hippocampi (VH) and 14 of them had additional electrodes in the piriform cortex. Animals were stimulated i n the left VH at afterdischarge threshold. There was no potentiation in sei zure response 4-7 weeks after MS. In contrast, ADRK produced not only kindl ing but also ongoing epileptogenesis resulting 4-7 weeks later in spontaneo us seizures and development of a prolonged convulsive state in response to the initially subconvulsive stimulus. Epileptiform activity during MS was m ostly restricted to VH, whereas during ADRK it spread widely among studied structures including piriform cortex. Afterdischarges during MS were elicit ed frequently but seizures did not progress beyond stage 2-3. During ADRK, afterdischarges were evoked less frequently but seizures reached stage 4-7 by the end of the 3rd and 4th stimulus days. The fully kindled state was no t reached at this time, but epileptogenic changes continued to progress. Se ven weeks after the initial stimulation, both groups demonstrated mossy fib er sprouting of similar intensity in VH. We suggest, (1) frequent but predo minantly local hippocampal afterdischarges induce mossy fiber sprouting, bu t this is not sufficient to produce significant enhancement in seizure susc eptibility, and (2) the involvement of extra-hippocampal structures, possib ly piriform cortex, and formation of an aberrant hippocampal-para-hippocamp al circuit is required to result in a condition of progressive epileptogene sis. (C) 1999 Elsevier Science B.V. All rights reserved.