Involvement of inward rectifier and M-type currents in carbachol-induced epileptiform synchronization

Abstract

Exposure to cholinergic agonists is a widely used paradigm to induce epileptogenesis in vivo and synchronous activity in brain slices maintained in vitro. However, the mechanisms underlying these effects remain unclear. Here, we used field potential recordings from the lateral entorhinal cortex in horizontal rat brain slices to explore whether two different K + currents regulated by muscarinic receptor activation, the inward rectifier (K IR ) and the M-type (K M ) currents, have a role in carbachol (CCh)-induced field activity, a prototypical model of cholinergic-dependent epileptiform synchronization. To establish whether K IR or K M blockade could replicate CCh effects, we exposed slices to blockers of these currents in the absence of CCh. K IR channel blockade with micromolar Ba 2+ concentrations induced interictal-like events with duration and frequency that were lower than those observed with CCh; by contrast, the K M blocker linopirdine was ineffective. Pre-treatment with Ba 2+ or linopirdine increased the duration of epileptiform discharges induced by subsequent application of CCh. Baclofen, a GABA B receptor agonist that activates K IR , abolished CCh-induced field oscillations, an effect that was abrogated by the GABA B receptor antagonist CGP 55845, and prevented by Ba 2+ . Finally, when applied after CCh, the K M activators flupirtine and retigabine shifted leftward the cumulative distribution of CChinduced event duration; this effect was opposite to what seen during linopirdine application under similar experimental conditions. Overall, our findings suggest that K IR rather than K M plays a major regulatory role in controlling CCh-induced epileptiform synchronization.

Neuroservice proconvulsive (NS-PC) set: A new platform of electrophysiology-based assays to determine the proconvulsive potential of lead compounds

“…Then, the carbachol concentration was raised to 10 μM and triggered EDs with a specific pattern: 2-3 low rate ED occurring at about 0.025 Hz, followed a succession of EDs occurring at about 5 Hz over 4 s (thus with a frequency in the theta band; 4-12 Hz). This pattern closely resemble the theta rhythms triggered by carbachol in vitro in hippocampal slices (Cataldi et al, 2011;Lévesque, Cataldi, Chen, Hamidi, & Avoli, 2017;Williams & Kauer, 1997). Although carbachol-induced theta rhythms in vitro was sometimes considered as a model of theta oscillations recorded in vivo, the cellular mechanisms responsible for the oscillatory activity substantially differ.…”

“…Although carbachol-induced theta rhythms in vitro was sometimes considered as a model of theta oscillations recorded in vivo, the cellular mechanisms responsible for the oscillatory activity substantially differ. Events triggered by carbachol rather correspond to interictal discharges observed in various models of epilepsy (Cataldi et al, 2011;Williams & Kauer, 1997). Carbachol-induced EDs mainly results from M1 muscarinic receptors activation.…”

Muscarinic acetylcholine receptor-mediated effects in slices from human epileptogenic cortex

“…These compounds were used to delineate the mAChRs involved in the cellular effects. In addition, we used the Mcurrent activator retigabine (Rundfeldt, 1997;Otto et al, 2002) and the M-current blocker linopirdine (Aiken et al, 1995), also known to modulate epileptiform activities in vitro (Cataldi et al, 2011). We selected established concentrations of agonist and antagonist based on a literature survey, a few pilot experiments and a preceding study in the rat neocortex (Gigout et al, 2012).…”

Models of drug-induced epileptiform synchronization in vitro

“…Prolonged periods of epileptiform synchronization have also been reported to occur in the entorhinal cortex during application of carbachol, another muscarinic receptor agonist (Dickson and Alonso, 1997;Cataldi et al, 2011). Interestingly, in the study by Dickson and Alonso (1997) small-amplitude field spikes could be recorded in the entorhinal cortex during application of carbachol and excitatory glutamatergic antagonists.…”

“…As in the in vitro 4AP model these field events were correlated to large-amplitude IPSPs that were abolished by GABA A receptor antagonists. It should be, however, noted that the ictal-like discharges induced by carbachol, especially when recorded from limbic areas such as the hippocampal CA3 subfield or the subiculum, are mainly characterized by prolonged series of regular field oscillations at 5-16 Hz, and thus they lack any clear "tonic" and "clonic" component as in the case of 4AP-induced ictal discharges (D'Antuono et al, 2001;Cataldi et al, 2011;M. Cataldi and M. Avoli, unpublished data).…”