Role of M-Type Potassium Channels Glutamatergic Synaptic Transmission and Status Epilepticus (IN5-1.003)

Abstract

Objective: Whether M-currents modulate glutamatergic synaptic transmission and whether the drugs that open these channels could terminate seizures induced by muscarinic stimulation. Background Muscarinic activation by pilocarpine and anologs result in seizures presumably by the inhibition of M-currents. Muscarinic stimulation modulates glutamatergic synaptic transmission but the mechanisms remain uncertain. Design/Methods: Whole-cell patch clamp recordings from CA3 and CA1 hippocampal pyramidal neurons and video EEG recoprdings from rats. Results: In voltage clamp recordings, XE-991 an M channel blocker increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs), but had no effect on their amplitude. XE-991 and its anolog linopordine also increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) but had no effect on their amplitude. M1 receptor agonist NcN-A-343 also increased the frequency of mEPSCs. The M-channel opener flupirtine had the effect opposite of XE-991. The XE-991 enhancement of mEPSCs frequency was not observed in calcium free external ACSF. When P/Q- or N-type calcium channel was blocked, the effect of XE-991 on mEPSCs was partially prevented. These data suggest that M-channel blockage increases presynaptic calcium dependent glutamate release in CA1 neurons. Current clamp recordings performed in CA3 neurons revealed that XE-991 depolarized membrane potential and increased burst firing. McN-A-343 had similar effect on CA3 neurons as XE-991. We then tested whether M-channel opener flupirtine could terminate status epilepticus (SE). Administration of flupirtine (50 mg/kg) and diazepam (10 mg/kg) individually 10 minutes after continuous EEG activity of first grade seizure was observed did not terminate SE; however, co-administration both drugs significantly reduced the length of SE, with 80% (4/5) rats returning to normal EEG within 90 minutes of treatment. Conclusions: Cholinergic activation causes depolarization of presynaptic CA3 neurons via M-channels, which activates calcium channels to increase glutamate release. Cholinergic inhibition of M-channel contributes to seizure generation.Drugs targeting M currents can terminate status epilepticus. Supported by: Congessionaly Directed Medical Research Program of the Department of Defense. NIH. Disclosure: Dr. Kapur has received (royalty or license fee or contractual rights) payments from a patent. Dr. Sun has nothing to disclose.