Neuronal hyperexcitability is a symptom characterizing several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). In the ALS bulbar form, hypoglossal motoneurons (HMs) are an early target for neurodegeneration because of their high vulnerability to metabolic insults. In recent years, our laboratory has developed an in vitro model of a brainstem slice comprising the hypoglossal nucleus in which HM neurodegeneration is achieved by blocking glutamate clearance with dl-threo-β-benzyloxyaspartate (TBOA), thus leading to delayed excitotoxicity. During this process, HMs display a set of hallmarks such as hyperexcitability (and network bursting), reactive oxygen species (ROS) generation and, finally, cell death. The present study aimed to investigate whether blocking early hyperexcitability and bursting with the anti-convulsant drug retigabine was sufficient to achieve neuroprotection against excitotoxicity. Retigabine is a selective positive allosteric modulator of the M-current (I ), an endogenous mechanism that neurons (comprising HMs) express to dampen excitability. Retigabine (10 μm; co-applied with TBOA) contrasted ROS generation, release of endogenous toxic factors into the HM cytoplasm and excitotoxicity-induced HM death. Electrophysiological experiments showed that retigabine readily contrasted and arrested bursting evoked by TBOA administration. Because neuronal I subunits (Kv7.2, Kv7.3 and Kv7.5) were expressed in the hypoglossal nucleus and in functionally connected medullary nuclei, we suggest that they were responsible for the strong reduction in network excitability, a potent phenomenon for achieving neuroprotection against TBOA-induced excitotoxicity. The results of the present study may have translational value for testing novel positive pharmacological modulators of the I under pathological conditions (including neurodegenerative disorders) characterized by excessive neuronal excitability.

Background and Purpose The KCNQ2 gene encodes for the Kv7.2 subunit of non‐inactivating potassium channels. KCNQ2‐related diseases range from autosomal dominant neonatal self‐limited epilepsy, often caused by KCNQ2 haploinsufficiency, to severe encephalopathies caused by KCNQ2 missense variants. In vivo and in vitro effects of the sodium channel blocker eslicarbazepine acetate (ESL) and eslicarbazepine metabolite (S‐Lic) in a mouse model of self‐limited neonatal epilepsy as a first attempt to assess the utility of ESL in the KCNQ2 disease spectrum was investigated. Experimental Approach Effects of S‐Lic on in vitro physiological and pathological hippocampal neuronal activity in slices from mice carrying a heterozygous deletion of Kcnq2 (Kcnq2+/−) and Kcnq2+/+ mice were investigated. ESL in vivo efficacy was investigated in the 6‐Hz psychomotor seizure model in both Kcnq2+/− and Kcnq2+/+ mice. Key Results S‐Lic increased the amplitude and decreased the incidence of physiological sharp wave–ripples in a concentration‐dependent manner and slightly decreased gamma oscillations frequency. 4‐Aminopyridine‐evoked seizure‐like events were blocked at high S‐Lic concentrations and substantially reduced in incidence at lower concentrations. These results were not different in Kcnq2+/+ and Kcnq2+/− mice, although the EC50 estimation implicated higher efficacy in Kcnq2+/−animals. In vivo, Kcnq2+/− mice had a lower seizure threshold than Kcnq2+/+ mice. In both genotypes, ESL dose‐dependently displayed protection against seizures. Conclusions and Implications S‐Lic slightly modulates hippocampal oscillations and blocks epileptic activity in vitro and in vivo. Our results suggest that the increased excitability in Kcnq2+/− mice is effectively targeted by S‐Lic high concentrations, presumably by blocking diverse sodium channel subtypes.