Function of Inhibitory Micronetworks Is Spared by Na⁺Channel-Acting Anticonvulsant Drugs

Abstract

The mechanisms of action of many CNS drugs have been studied extensively on the level of their target proteins, but the effects of these compounds on the level of complex CNS networks that are composed of different types of excitatory and inhibitory neurons are not well understood. Many currently used anticonvulsant drugs are known to exert potent use-dependent blocking effects on voltage-gated Na ϩ channels, which are thought to underlie the inhibition of pathological high-frequency firing. However, some GABAergic inhibitory neurons are capable of firing at very high rates, suggesting that these anticonvulsants should cause impaired GABAergic inhibition. We have, therefore, studied the effects of anticonvulsant drugs acting via use-dependent block of voltage-gated Na ϩ channels on GABAergic inhibitory micronetworks in the rodent hippocampus. We find that firing of pyramidal neurons is reliably inhibited in a use-dependent manner by the prototypical Na ϩ channel blocker carbamazepine. In contrast, a combination of intrinsic and synaptic properties renders synaptically driven firing of interneurons essentially insensitive to this anticonvulsant. In addition, a combination of voltage imaging and electrophysiological experiments reveal that GABAergic feedforward and feedback inhibition is unaffected by carbamazepine and additional commonly used Na ϩ channel-acting anticonvulsants, both in control and epileptic animals. Moreover, inhibition in control and epileptic rats recruited by in vivo activity patterns was similarly unaffected. These results suggest that sparing of inhibition is an important principle underlying the powerful reduction of CNS excitability exerted by anticonvulsant drugs.

The pervasive reduction of GABA-mediated synaptic inhibition of principal neurons in the hippocampus during status epilepticus

“…An important question to be addressed in a future study is whether these activity-dependent changes in inhibition and excitation are limited to the principal neurons or also effect interneurons and the recruitment of inhibitory networks during SE (Pothmann et al, 2014). This further characterization of pre- and post-synaptic changes across the entire hippocampal network is necessary to better define the cellular mechanisms by which seizure termination fails and this dynamic, evolving neurological emergency persists.…”

Microcircuits and their interactions in epilepsy: is the focus out of focus?

“…To resolve this paradox, a study recently addressed the effects of Na + channel blockers (e.g., the anti-convulsant drugs carbamazepine, phenytoin, and lamotrigine) on different cell types. These compounds specifically reduced repetitive firing in pyramidal neurons, but not in FS or other interneurons 57 . The AEDs also did not affect recruitment of inhibition during repetitive activity.…”

Activity of the anticonvulsant lacosamide in experimental and human epilepsy via selective effects on slow Na+ channel inactivation

“…Male Wistar rats (180–200 g) were housed under a 12‐h light/dark cycle with unrestricted access to food and water. Rats were injected with a single high dose of the muscarinic agonist pilocarpine (340 mg/kg, administered intraperitoneally), which induced behaviorally detected status epilepticus (SE) in most (~80%) animals . Peripheral muscarinic effects were reduced by prior administration of methyl‐scopolamine (1 mg/kg, administered intraperitoneally [i.p.…”

“…Rats were injected with a single high dose of the muscarinic agonist pilocarpine (340 mg/kg, administered intraperitoneally), which induced behaviorally detected status epilepticus (SE) in most (~80%) animals. [13][14][15][16][17] Peripheral muscarinic effects were reduced by prior administration of methyl-scopolamine (1 mg/kg, administered intraperitoneally [i.p. ]; 30 min before injecting pilocarpine).…”