Abstracts

RATIONALE: The M-current is a sustained K⁺ current active in the depolarized range that regulates neuronal response to synaptic input. Subunits that compose the M-channel, KCNQ2 and KCNQ3, are mutated and hypofunctional in an inheritable idiopathic epilepsy, benign familial neonatal convulsions. These findings indicate the M-current may be important in regulating epileptic activity and could be a useful clinical target for new anti-epileptic drugs. Potentiation of the M-current is an important mechanism by which some inhibitory neuropeptides regulate hippocampal excitability. We therefore examined the role of the M-current in epileptiform and seizure models in hippocampus, including its contribution to the anti-epileptic actions of the inhibitory neuropeptides somatostatin (SST) and nociceptin (NOC).
METHODS: We used rat hippocampal slices to record epileptiform bursts generated in Mg⁺⁺-free artificial cerebral spinal fluid or raised (7.5 mM) extracellular K⁺. Both intracellular and extracellular recording techniques were used. We examined the actions of the M-current blocker linopirdine in these models in CA1 and CA3. Further, we compared reduction of epileptiform activity by neuropeptides alone and with co-application of linopirdine to determine the contribution of the M-current to their anti-epileptic activity.
RESULTS: In both CA1 and CA3, blocking the M-current with linopirdine increased the duration and intensity of epileptiform bursts and sometimes decreased the burst rate. Specifically, blocking the M-current increased the number of secondary afterdischarges per burst. Further, the transition from interictal to ictal bursting was more likely to occur in the presence of linopirdine. In Mg⁺⁺-free ACSF and elevated K⁺ epileptiform models, linopirdine did not attenuate inhibition of bursting by NOC, even though this peptide augments the M-current. Instead, anti-epileptic actions of NOC were partially blocked by 150 [mu]M Ba⁺⁺, suggesting postsynaptic activation of inward rectifier K⁺ currents contributes to NOC inhibition of epileptiform bursting. In contrast, linopirdine attenuated the ability of SST to inhibit bursting in CA1 but not CA3, suggesting augmentation of the M-current by SST contributes to its anti-epileptic actions.
CONCLUSIONS: Our results show the M-current is involved in regulation of epileptiform burst duration in CA1 and CA3. NOC inhibition of bursting is dependent on activation of inward rectifier but not M-currents. Augmentation of the M-current contributes to the anti-epileptic actions of SST in CA1 but not CA3. This regional difference may be due to the higher M-current density in CA1.
Support: NIH grants NS 38633 and MH 44346.