Increased susceptibility to acetylcholine in the entorhinal cortex of pilocarpine-treated rats involves alterations in KCNQ channels

TY - JOUR

T1 - Increased susceptibility to acetylcholine in the entorhinal cortex of pilocarpine-treated rats involves alterations in KCNQ channels

AU - Maslarova, Anna

AU - Salar, Seda

AU - Lapilover, Ezequiel

AU - Friedman, Alon

AU - Veh, Rüdiger W

AU - Heinemann, Uwe

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/8

Y1 - 2013/8

N2 - In models of temporal lobe epilepsy, in-vitro exposure of the entorhinal cortex (EC) to low concentrations of acetylcholine (ACh) induces muscarinic-dependent seizure-like events. Potassium channels from the KCNQ/Kv7 family, which close upon activation of muscarinic receptors, are mutated in several epileptic syndromes such as benign familial neonatal convulsions (KCNQ2/KCNQ3) and sudden unexplained death in epilepsy (KCNQ1). Therefore, we tested the hypothesis whether the ictogenic effect of ACh involves alterations of KCNQ channels. In horizontal temporo-hippocampal slices from pilocarpine-treated chronically epileptic rats, field potential recordings of epileptiform activity were performed in response to the application of ACh, the KCNQ blocker linopirdine, and KCNQ agonists. In the EC of control rats, ACh (20 and 50 μM) induced nested fast activity in the range of 15-20 Hz riding on <1 Hz slow oscillations. By contrast, in slices from pilocarpine-treated rats, 5 μM ACh was sufficient to induce interictal discharges that frequently transformed to epileptiform events at 20 μM ACh. While the non-specific KCNQ/Kv7 channel blocker linopirdine (20 and 50 μM) had no effect in control animals, in slices from epileptic rats it induced interictal discharges or seizure-like events. These could be blocked by the unspecific KCNQ/Kv7 agonist retigabine and attenuated by the Kv7.1 agonist L364-373. Immunohistochemistry revealed reduced expression of KCNQ2 and KCNQ3 in the EC and of KCNQ3-positive dendrites in the subiculum of epileptic rats. These results indicate that channels of the KCNQ family are key regulators of seizure susceptibility and their decreased availability in the epileptic tissue may reduce seizure threshold and contribute to ictogenesis.

AB - In models of temporal lobe epilepsy, in-vitro exposure of the entorhinal cortex (EC) to low concentrations of acetylcholine (ACh) induces muscarinic-dependent seizure-like events. Potassium channels from the KCNQ/Kv7 family, which close upon activation of muscarinic receptors, are mutated in several epileptic syndromes such as benign familial neonatal convulsions (KCNQ2/KCNQ3) and sudden unexplained death in epilepsy (KCNQ1). Therefore, we tested the hypothesis whether the ictogenic effect of ACh involves alterations of KCNQ channels. In horizontal temporo-hippocampal slices from pilocarpine-treated chronically epileptic rats, field potential recordings of epileptiform activity were performed in response to the application of ACh, the KCNQ blocker linopirdine, and KCNQ agonists. In the EC of control rats, ACh (20 and 50 μM) induced nested fast activity in the range of 15-20 Hz riding on <1 Hz slow oscillations. By contrast, in slices from pilocarpine-treated rats, 5 μM ACh was sufficient to induce interictal discharges that frequently transformed to epileptiform events at 20 μM ACh. While the non-specific KCNQ/Kv7 channel blocker linopirdine (20 and 50 μM) had no effect in control animals, in slices from epileptic rats it induced interictal discharges or seizure-like events. These could be blocked by the unspecific KCNQ/Kv7 agonist retigabine and attenuated by the Kv7.1 agonist L364-373. Immunohistochemistry revealed reduced expression of KCNQ2 and KCNQ3 in the EC and of KCNQ3-positive dendrites in the subiculum of epileptic rats. These results indicate that channels of the KCNQ family are key regulators of seizure susceptibility and their decreased availability in the epileptic tissue may reduce seizure threshold and contribute to ictogenesis.

KW - Acetylcholine

KW - Animals

KW - Calcium Channel Agonists

KW - Calcium Channel Blockers

KW - Entorhinal Cortex

KW - Evoked Potentials

KW - Immunohistochemistry

KW - Indoles

KW - KCNQ Potassium Channels

KW - Male

KW - Muscarinic Agonists

KW - Nerve Net

KW - Pilocarpine

KW - Potassium Channel Blockers

KW - Pyridines

KW - Rats

KW - Rats, Wistar

KW - Seizures

KW - Status Epilepticus

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1016/j.nbd.2013.02.016

DO - 10.1016/j.nbd.2013.02.016

M3 - SCORING: Journal article

C2 - 23583611

VL - 56

SP - 14

EP - 24

JO - NEUROBIOL DIS

JF - NEUROBIOL DIS

SN - 0969-9961

ER -