Abstract
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.
Highlights
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a rapidly progressive neurodegenerative disease that targets motor neurons
Our results indicate that the SOD1G93A lumbar spinal cord (SC) is less enriched with 5-HT-ir fibres and exhibits a lower 5-HT content than the lumbar SC of WT littermates
We recently described reduced GABA/glycine synaptic input in E17.5 lumbar SOD1G93A MNs that might reflect a developmental delay in the maturation of SOD1G93A SCs compared to WT SCs
Summary
Amyotrophic lateral sclerosis (ALS), known as Lou Gehrig’s disease, is a rapidly progressive neurodegenerative disease that targets motor neurons. We have shown that the maturation of the inhibitory system in the mouse embryonic SC is controlled by descending 5-HT raphe inputs [15,16] This inhibitory system mostly develops after E15.5, when a switch occurs, inducing a substantial drop in the intracellular chloride concentration [Cl−]i in lumbar motoneurons (MNs) and rendering GABA unable to provide excitation [17]. We show that exogenous applications of 5-HT exert potent hyperpolarizing effects on the ECl, assessed here as the reversal potential of GABAAR (EGABAAR) This leads to the conclusion that the lack of 5-HT innervation in the prenatal SC may be responsible for the alteration in chloride homeostasis in SOD1G93A spinal lumbar MNs and may explain the neurodevelopmental features of ALS that we recently described in the SOD1G93A mouse [3,21]
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