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Patients with Taylor's type focal cortical dysplasia (FCD) present with seizures that are often medically intractable. Here, we attempted to identify the cellular and pharmacological mechanisms responsible for this epileptogenic state by using field potential and K+-selective recordings in neocortical slices obtained from epileptic patients with FCD and, for purposes of comparison, with mesial temporal lobe epilepsy (MTLE), an epileptic disorder that, at least in the neocortex, is not characterized by any obvious structural aberration of neuronal networks. Spontaneous epileptiform activity was induced in vitro by applying 4-aminopyridine (4AP)-containing medium. Under these conditions, we could identify in FCD slices a close temporal relationship between ictal activity onset and the occurrence of slow interictal-like events that were mainly contributed by GABAA receptor activation. We also found that in FCD slices, pharmacological procedures capable of decreasing or increasing GABAA receptor function abolished or potentiated ictal discharges, respectively. In addition, the initiation of ictal events in FCD tissue coincided with the occurrence of GABAA receptor-dependent interictal events leading to [K+]o elevations that were larger than those seen during the interictal period. Finally, by testing the effects induced by baclofen on epileptiform events generated by FCD and MTLE slices, we discovered that the function of GABAB receptors (presumably located at presynaptic inhibitory terminals) was markedly decreased in FCD tissue. Thus, epileptiform synchronization leading to in vitro ictal activity in the human FCD tissue is initiated by a synchronizing mechanism that paradoxically relies on GABAA receptor activation causing sizeable increases in [K+]o. This mechanism may be facilitated by the decreased ability of GABAB receptors to control GABA release from interneuron terminals.

Several cytokines have short-term effects on synaptic transmission and plasticity that are thought to be mediated by the activation of intracellular protein kinases. We have studied the effects of interleukin-6 (IL-6) on the expression of paired pulse facilitation (PPF), posttetanic potentiation (PTP), and long-term potentiation (LTP) in the CA1 region of the hippocampus as well as on the activation of the signal transducer and activator of transcription-3 (STAT3), the mitogen-activated protein kinase ERK (MAPK/ERK), and the stress-activated protein kinase/c-Jun NH 2 -terminal kinase (SAPK/JNK). IL-6 induced a marked and dose-dependent decrease in the expression of PTP and LTP that could be counteracted by the simultaneous treatment with the tyrosine kinase inhibitor lavendustin A (LavA) but did not significantly affect PPF. The IL-6-induced inhibition of PTP and LTP was accompanied by a simulation of STAT3 tyrosine phosphorylation and an inhibition of MAPK/ERK dual phosphorylation, in the absence of changes in the state of activation of SAPK/JNK. Both effects of IL-6 on STAT3 and MAPK/ERK activation were effectively counteracted by LavA treatment. The results indicate that tyrosine kinases and MAPK/ERK are involved in hippocampal synaptic plasticity and may represent preferential intracellular targets for the actions of IL-6 in the adult nervous system. Key Words: Long-term potentiation-Posttetanic potentiation-Tyrosine phosphorylation-Mitogenactivated protein kinase -Signal transducer and activator of transcription-3 (STAT3). J. Neurochem. 75, 634 -643 (2000).The molecular mechanisms underlying changes in synaptic efficacy are beginning to be elucidated and, in most cases, involve long-lasting changes at both pre-and postsynaptic levels mediated by the activation of intracellular signal transduction systems as well as by changes in gene expression. There is increasing evidence that protein kinases such as protein kinase C, Ca 2ϩ / calmodulin-dependent protein kinase II, protein kinase A, Src-family protein kinases, and the mitogen-activated protein kinase ERK (MAPK/ERK) are intimately involved in the expression of long-term potentiation (LTP) in the hippocampus (Grant et al

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SUMMARYPurpose: We established the effects of the antiepileptic drugs (AEDs) carbamazepine (CBZ), topiramate (TPM), and valproic acid (VPA) on the epileptiform activity induced by 4-aminopyridine (4AP) in the rat entorhinal cortex (EC) in an in vitro brain slice preparation. Methods: Brain slices were obtained from Sprague-Dawley rats (200-250 g). Field and intracellular recordings were made from the EC during bath application of 4AP (50 lM). AEDs, and in some experiments, picrotoxin were bath applied concomitantly. Results: Prolonged (>3 s), ictal-like epileptiform events were abolished by CBZ (50 lM), TPM (50 lM), and VPA (1 mM), whereas shorter (<3 s) interictal-like discharges continued to occur, even at concentrations up to 4-fold as high. c-Aminobutyric acid (GABA) A -receptor antagonism changed the 4AP-induced activity into recurrent interictallike events that were not affected by CBZ or TPM, even at the highest concentrations. To establish whether these findings reflected the temporal features of the epileptiform discharges, we tested CBZ and TPM on 4AP-induced epileptiform activity driven by stimuli delivered at 100-, 10-, and 5-s intervals; these AEDs reduced ictal-like responses to stimuli at 100-s intervals at nearly therapeutic concentrations, but did not influence shorter interictal-like events elicited by stimuli delivered every 10 or 5 s. Conclusions: We conclude that the AED ability to control epileptiform synchronization in vitro depends mainly on activity-dependent characteristics such as discharge duration. Our data are in keeping with clinical evidence indicating that interictal activity is unaffected by AED levels that are effective to stop seizures.

We employed in vitro and ex vivo imaging tools to characterize the function of limbic neuron networks in pilocarpine-treated and age-matched, nonepileptic control (NEC) rats. Pilocarpinetreated animals represent an established model of mesial temporal lobe epilepsy. Intrinsic optical signal (IOS) analysis of hippocampal-entorhinal cortex (EC) slices obtained from epileptic rats 3 wk after pilocarpine-induced status epilepticus (SE) revealed hyperexcitability in many limbic areas, but not in CA3 and medial EC layer III. By visualizing immunopositivity for FosB/∆FosB-related proteins-which accumulate in the nuclei of neurons activated by seizures-we found that: (1) 24 h after SE, FosB/∆FosB immunoreactivity was absent in medial EC layer III, but abundant in dentate gyrus, hippocampus proper (including CA3) and subiculum; (2) FosB/∆FosB levels progressively diminished 3 and 7 d after SE, whereas remaining elevated (p < 0.01) in subiculum; (3) FosB/∆FosB levels sharply increased 2 wk after SE (and remained elevated up to 3 wk) in dentate gyrus and in most of the other areas but not in CA3. A conspicuous neuronal damage was noticed in medial EC layer III, whereas hippocampus was more preserved. IOS analysis of the stimulusinduced responses in slices 3 wk after SE demonstrated that IOSs in CA3 were lower (p < 0.05) than in NEC slices following dentate gyrus stimulation, but not when stimuli were delivered in CA3. These findings indicate that CA3 networks are hypoactive in comparision with other epileptic limbic areas. We propose that this feature may affect the ability of hippocampal outputs to control epileptiform synchronization in EC.