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In this paradigm, HMs display hyperexcitability, collective bursting and eventually cell death.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The results of the present study show that pharmacological up\u2010regulation of a K<jats:sup>+<\/jats:sup> current (M\u2010current), via application of the anti\u2010convulsant retigabine, prevented all hallmarks of HM excitotoxicity, comprising bursting, generation of reactive oxygen species, expression of toxic markers and cell death.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Our data may have translational value to develop new treatments against neurological diseases by using positive pharmacological modulators of the M\u2010current.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>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 <jats:italic>in vitro<\/jats:italic> model of a brainstem slice comprising the hypoglossal nucleus in which HM neurodegeneration is achieved by blocking glutamate clearance with <jats:sc>dl<\/jats:sc>\u2010threo\u2010\u03b2\u2010benzyloxyaspartate (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\u2010convulsant drug retigabine was sufficient to achieve neuroprotection against excitotoxicity. Retigabine is a selective positive allosteric modulator of the M\u2010current (<jats:italic>I<\/jats:italic><jats:sub>M<\/jats:sub>), an endogenous mechanism that neurons (comprising HMs) express to dampen excitability. Retigabine (10\u00a0\u03bc<jats:sc>m<\/jats:sc>; co\u2010applied with TBOA) contrasted ROS generation, release of endogenous toxic factors into the HM cytoplasm and excitotoxicity\u2010induced HM death. Electrophysiological experiments showed that retigabine readily contrasted and arrested bursting evoked by TBOA administration. Because neuronal <jats:italic>I<\/jats:italic><jats:sub>M<\/jats:sub> 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\u2010induced excitotoxicity. The results of the present study may have translational value for testing novel positive pharmacological modulators of the <jats:italic>I<\/jats:italic><jats:sub>M<\/jats:sub> under pathological conditions (including neurodegenerative disorders) characterized by excessive neuronal excitability.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp275906","type":"journal-article","created":{"date-parts":[[2018,5,8]],"date-time":"2018-05-08T04:24:54Z","timestamp":1525753494000},"page":"2611-2629","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Functional up\u2010regulation of the M\u2010current by retigabine contrasts hyperexcitability and excitotoxicity on rat hypoglossal motoneurons"],"prefix":"10.1113","volume":"596","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4538-2578","authenticated-orcid":false,"given":"Filippo","family":"Ghezzi","sequence":"first","affiliation":[{"name":"Department of Neuroscience International 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