Summary: Purpose:The anticonvulsants phenytoin (PHT), carbamazepine (CBZ), and gabapentin (GBP) are commonly used in the treatment of temporal lobe epilepsy. Ca" current modulation has been proposed to contribute to the antiepileptic activity of these drugs. The purpose of this study was to determine the effects of these anticonvulsants on voltage-dependent calcium channels in pathologically altered neurons from patients with chronic temporal lobe epilepsy.Methods: Acutely isolated human hippocampal granule cells were examined by using the whole-cell configuration of the patch-clamp technique.Results: PHT and CBZ produced a reversible, concentrationdependent inhibition of high-voltage-activated (HVA) Ca2' currents without affecting voltage-dependent activation. The concentration-response curves of PHT and CBZ indicated maximal inhibition of 35 and 65%, respectively, with halfmaximal inhibition being obtained at 89 and 244 ph4, respectively. At therapeutic cerebrospinal fluid (CSF) concentrations, HVA currents were not significantly altered by PHT and CBZ. However, PHT but not CBZ showed a reduction of HVA currents of 16% at a therapeutic whole-brain concentration of 80 FM. In contrast to CBZ, PHT produced a small hyperpolarizing shift in the voltage dependence of steady-state inactivation. PHT, 80 ph4, shifted the potential of half-maximal inactivation by -3.1 f 0.5 mV (p < 0.05). GBP, which was recently found to bind to the a$ subunit of a neuronal Ca" channel, showed no modulation of Ca2+ conductances.Conclusions: These results suggest that, in contrast to GBP and CBZ, modulation of postsynaptic Ca2+ channels can contribute to the anticonvulsant action of PHT in human hippocampal granule cells.

Summary:Purpose: Recent data suggested a role for glial cells in epilepsy. This study sought to identify and functionally characterize AMPA receptors expressed by astrocytes in human hippocampal tissue resected from patients with intractable temporal lobe epilepsy.Methods: Patch-clamp and fast application methods were combined to investigate astrocytes in situ and after fresh isolation from the stratum radiatum of the hippocampal CA1 subfield. Relying on presurgical and histopathologic analysis, we divided human specimens into two groups, Ammon's horn sclerosis (AHS) and lesion-associated epilepsy.Results: Fast application of glutamate and kainate evoked receptor currents in all cells studied. Reversal-potential analysis revealed an intermediate Ca 2+ permeability of the receptor channels that did not vary between the two groups of patients.However, preapplication of the AMPA receptor-specific modulator, cyclothiazide, disclosed differences in flip-flop splicing. This treatment considerably enhanced the receptor conductance, with potentiation being significantly stronger in cells from AHS specimens compared with lesion-associated cells, suggesting upregulation of AMPA receptor flip splice variants in astrocytes of the sclerotic tissue.Conclusions: Compelling evidence has been accumulated showing direct and rapid signaling between neurons and glial cells. Our data suggest that in AHS patients, neuronally released glutamate will lead to an enhanced and prolonged depolarization of astrocytes, which might be involved in seizure generation and spread in this particular condition of human temporal lobe epilepsy.

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Summary:Purpose: Metabotropic glutamate receptors (mGluRs) might be promising new drug targets for the treatment of epilepsy because the expression of certain mGluRs is regulated in epilepsy and because activation of mGluRs results in distinctive anti-and proconvulsant effects. Therefore, we examined how rnGluR activation modulates high-voltageactivated (HVA) Ca2' channels.Methods: Whole-cell patch-clamp recordings were obtained from granule cells and interneuron-like cells acutely isolated from the dentate gyrus of patients with pharmacoresistent temporal lobe epilepsy. Results:Agonists selective for either group I or group II mGluRs rapidly and reversibly reduced HVA currents in most dentate gyrus cells. These modulatory effects were inhibited by the respective group I and group IT mGluR antagonists. The specific Ca' " channel antagonists nifedipine and w-conotoxin GVIA potently occluded the effects of group I and II mGluR agonists, respectively, indicating that group I mGluRs acted on L-type channels and group II mGluRs affected N-type channels. About two thirds of the responsive neurons were sensitive either to group I or group II mGluRs, whereas a minority of cells showed effects to agonists of both groups, indicating a variable mGluR expression pattern. Metabotropic (mGluRs) and ionotropic glutamate receptors belong to the family of glutamate receptors. In contrast to the ionotropic receptors, which form ligandgated ion channels, mGluRs influence the activity of membrane enzymes and ion channels by means of G proteins. Thus, mGluRs modulate, rather than mediate, fast synaptic transmission. The mGluRs represent a family of eight subtypes, termed mGluR1 to mGluR8, which are divided into three groups on the basis of sequence homology, transduction pathways, and pharmacologic properties revealed in recombinant expression systems. Group I consists of mGluRl and mGluR5, which are coupled to phosphoinositide hydrolysis. Members of group I1 (mGluR2 and 3) and group LU (mGluR4,