Entorhinal cortex-subiculum interactions in an experimental model of mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (MTLE) patients present with seizuresinvolving the limbic system and with a pattern of brain damage characterizedby neuronal loss in CA1/CA3 areas, dentate hilus, and entorhinalcortex (EC), layer III (Houser CR. Adv Neurol 1999;79:743–61). Similarfindings are seen in laboratory animals following pilocarpine injection(Turski WA, et al. Behav Brain Res 1983;9:315–35). This procedure inducesan initial convulsive response, which is followed within 2–3 weeksby recurrent seizures. Limbic network hyperexcitability in MTLE andin animal models results from seizure-induced brain damage leading to(a) synaptic reorganization (Cavazos JE, et al. J Neurosci 1991;11:2795–803; Houser CR. Adv Neurol 1999;79:743–61) and (b) changes inGABAreceptor–mediated inhibition (Buhl EH, et al. Science 1996;271:369–7;Doherty J, Dingledine R. J Neurosci 2001;21:2048–57. However, it isunclear how these changes lead to a chronic epileptic condition.CA3-driven interictal activity induced in normal brain tissue by epileptogenicstimuli inhibits the EC from generating ictal discharges (BarbarosieM, Avoli M. J Neurosci 1997;17:9308–14), suggesting that CA3damage causes a decrease of hippocampal output activity that wouldrelease EC ictogenesis and establish a chronic epileptic condition. Accordingly,slices obtained from pilocarpine-treated epileptic mice respondto 4-aminopyridine (4AP) application by generating (a) CA3-driven interictal activity that is less frequent than in nonepileptic control(NEC) tissue, and (b) ictal discharges that do not disappear overtime and propagate to the CA1-subiculum via the temporoammonic path(D’Antuono M, et al. J Neurophysiol 2002;87:634–9). From these findings,we predicted that limbic seizures result from EC–subiculum interactions.Using brain slices obtained from pilocarpine-treated, epilepticrats, we found that decreased CA3 output function, along with reverberationbetween EC and subiculum networks, lead to in vitro epileptogenesis.First, intense activation of EC and subiculum was identifiedwith intrinsic optical signal (IOS) recordings in pilocarpine-treated, butnot in NEC slices. Second, using field potential recordings during 4APapplication, we established that CA3-driven interictal activity occursat lower frequency in pilocarpine-treated slices and that disconnectionof the EC from the subiculum attenuates 4AP-induced ictal dischargesin pilocarpine-treated, but not in NEC slices. Third, the distributionof FosB/FosB-related proteins in epileptic tissue demonstrated distinctpatterns overlapping those seen with IOS recordings, with the highestintensity in layer III of the lateral EC.In conclusion, our data show that hippocampal damage in epilepticrats, and perhaps in MTLE patients, hampers the ability of CA3 outputactivity to control ictogenesis in the EC. Such a process is reinforced byinteractions between subiculum and EC networks.