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Open AccessArticle

Implication of 5-HT in the Dysregulation of Chloride Homeostasis in Prenatal Spinal Motoneurons from the G93A Mouse Model of Amyotrophic Lateral Sclerosis

University of Bordeaux, CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(3), 1107; https://doi.org/10.3390/ijms21031107
Received: 12 January 2020 / Revised: 4 February 2020 / Accepted: 5 February 2020 / Published: 7 February 2020
(This article belongs to the Special Issue Serotonin in Health and Disease)
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron degeneration and muscle paralysis. The early presymptomatic onset of abnormal processes is indicative of cumulative defects that ultimately lead to a late manifestation of clinical symptoms. It remains of paramount importance to identify the primary defects that underlie this condition and to determine how these deficits lead to a cycle of deterioration. We recently demonstrated that prenatal E17.5 lumbar spinal motoneurons (MNs) from SOD1G93A mice exhibit a KCC2-related alteration in chloride homeostasis, i.e., the EGABAAR is more depolarized than in WT littermates. Here, using immunohistochemistry, we found that the SOD1G93A lumbar spinal cord is less enriched with 5-HT descending fibres than the WT lumbar spinal cord. High-performance liquid chromatography confirmed the lower level of the monoamine 5-HT in the SOD1G93A spinal cord compared to the WT spinal cord. Using ex vivo perforated patch-clamp recordings of lumbar MNs coupled with pharmacology, we demonstrated that 5-HT strongly hyperpolarizes the EGABAAR by interacting with KCC2. Therefore, the deregulation of the interplay between 5-HT and KCC2 may explain the alteration in chloride homeostasis detected in prenatal SOD1G93A MNs. In conclusion, 5-HT and KCC2 are two likely key factors in the presymptomatic phase of ALS, particular in familial ALS involving the SOD1G93A mutation. View Full-Text
Keywords: ALS; development; SOD1G93A mouse; 5-HT; chloride homeostasis; GABA/glycine; perforated patch-clamp; spinal cord; motoneuron ALS; development; SOD1G93A mouse; 5-HT; chloride homeostasis; GABA/glycine; perforated patch-clamp; spinal cord; motoneuron
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Martin, E.; Cazenave, W.; Allain, A.-E.; Cattaert, D.; Branchereau, P. Implication of 5-HT in the Dysregulation of Chloride Homeostasis in Prenatal Spinal Motoneurons from the G93A Mouse Model of Amyotrophic Lateral Sclerosis. Int. J. Mol. Sci. 2020, 21, 1107.

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