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EURON and THEME joint PhD meeting

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84<br />

<strong>EURON</strong> <strong>and</strong> <strong>THEME</strong> <strong>joint</strong> <strong>meeting</strong> 2011<br />

Effects of anticonvulsant drugs on hippocampal<br />

inhibitory microcircuits in the epileptic hippocampus<br />

Leonie Pothmann, Heinz Beck<br />

Department of Epileptology <strong>and</strong> Life&Brain Center, University Bonn, Sigmund-Freud-Str. 25, 53105 Bonn,<br />

Germany.<br />

The anticonvulsant carbamazepine (CBZ) acts via inhibition of voltage-gated<br />

Na + channels, showing an increase of inhibition when neurons fire at high<br />

frequencies. This use-dependent block is thought to be important in mediating<br />

the inhibition of pathological high-frequency seizure activity. However, some<br />

inhibitory interneuron types are capable of firing at very high rates, suggesting<br />

that CBZ should cause impaired GABAergic inhibition, <strong>and</strong> consequently increase<br />

excitability.<br />

Therefore, we examined the effects of CBZ on different cell types in the rat<br />

hippocampus. We found that pyramidal cell firing was inhibited by CBZ, as<br />

expected. However, interneurons that predominantly target pyramidal cell<br />

somata (group I), <strong>and</strong> interneurons targeting the apical dendritic tuft of<br />

pyramidal neurons (group II) did not show significant effects of CBZ. A third<br />

group of interneurons innervating the proximal dendrites of pyramidal cells in<br />

stratum oriens <strong>and</strong> stratum radiatum was affected by CBZ, showing a decrease<br />

of 44 % in maximal firing rate. To determine the impact of this reduction on<br />

inhibitory micronetworks we recruited feed-back <strong>and</strong> feed-forward inhibition<br />

of CA1 pyramidal cells by electrical stimulation of CA1 <strong>and</strong> CA3 pyramidal cell<br />

axons, respectively. At stimulation frequencies of 50 Hz, neither feed-back nor<br />

feed-forward inhibition was disturbed.<br />

In the pilocarpine model of chronic epilepsy we found marked changes in the<br />

responsiveness of different cell types: pyramidal cells showed a significant<br />

decrease of 14 % in the response to CBZ, whereas group I interneurons that<br />

where unresponsive in control animals now showed a block of 40 % in maximal<br />

firing rate. In contrast the pronounced effect on group III interneurons was lost in<br />

epileptic animal whereas the resistance of group II interneurons was unchanged.<br />

These data suggest differences in the properties of Na+ channels of different cell<br />

types, <strong>and</strong> that epileptogenesis leads to a marked change in the network effects<br />

of anticonvulsant drugs.

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