Desynchronisation of spontaneously recurrent experimental seizures proceeds with a single rhythm.

Here we investigate the temporal properties of recurrent seizure-like events (SLEs) in a low-[Mg(2+)] model of experimental epilepsy. Simultaneous intra- and extracellular electric signals were recorded in the CA3 region of rat hippocampal slices whereby cytosolic [Ca(2+)] transients were imaged by fluorescence detection. Recurrence pattern analysis was applied to give a measure of synchrony of simultaneously recorded intra- and extracellular electric signals and the SLE frequencies were extracted by complex wavelet analysis. Slices from the juvenile, but not the young adult rats, displayed several high-amplitude triplets of electric and [Ca(2+)] transients, termed paroxysmal spikes, followed by an SLE. Occurrence of the full-blown SLE was associated with decreased synaptic activity between the paroxysmal spikes that were seen as incomplete SLE starting sequences. The time series of recurrent SLEs provide evidence for a single SLE rhythm as continuously declining from about 200 Hz to below 1 Hz at the onset and termination of SLE, respectively, with an intermediate spectral discontinuity, tentatively identified with the tonic/clonic transition. All other frequency components were the harmonics of the fundamental rhythm, whereby the gamma and the theta band oscillations were not detected as separate activities. Recurrence showed decreasing temporal synchrony of intra- and extracellular signals during the SLE, suggesting that coincidence is destroyed by the SLE. Blockade of gap junctions with 200 microM carbenoxolone ceased recurrent SLEs. Release of gap junction blockade shortened both SLEs and their tonic phase indicating that persistent changes occurred via an altered gap junction coupling. We conclude that the initially precise temporal synchrony is gradually destroyed during ictal events with a single rhythm of continuously decreasing frequency. Blockade of gap junction coupling might prevent epileptic synchronisation.

Inhibition of voltage-gated calcium channels by fluoxetine in rat hippocampal pyramidal cells.

Fluoxetine, an antidepressant which is used world-wide, is a prominent member of the class of selective serotonin re-uptake inhibitors. Recently, inhibition of voltage-gated Na(+) and K(+) channels by fluoxetine has also been reported. We examined the effect of fluoxetine on voltage-gated calcium channels using the patch-clamp technique in the whole-cell configuration. In hippocampal pyramidal cells, fluoxetine inhibited the low-voltage-activated (T-type) calcium current with an IC(50) of 6.8 microM. Fluoxetine decreased the high-voltage-activated (HVA) calcium current with an IC(50) between 1 and 2 microM. Nifedipine and omega-conotoxin GVIA inhibited the HVA current by 24% and 43%, respectively. Fluoxetine (3 microM), applied in addition to nifedipine or omega-conotoxin, further reduced the current. When fluoxetine (3 microM) was applied first neither nifedipine nor omega-conotoxin attenuated the remaining component of the HVA current. This observation indicates that fluoxetine inhibits both L- and N-type currents. In addition, fluoxetine inhibited the HVA calcium current in carotid body type I chemoreceptor cells and pyramidal neurons prepared from prefrontal cortex. In hippocampal pyramidal cells high K(+)-induced seizure-like activity was inhibited by 1 microM fluoxetine; the mean burst duration was shortened by an average of 44%. These results provide evidence for inhibition of T-, N- and L-type voltage-gated calcium channels by fluoxetine at therapeutically relevant concentrations.