Dynamic interplay between H-current and M-current controls motoneuron hyperexcitability in amyotrophic lateral sclerosis

• Published in: Cell death & disease Vol. 10; no. 4; p. 310
• Main Authors: Buskila, Yossi, Kékesi, Orsolya, Bellot-Saez, Alba, Seah, Winston, Berg, Tracey, Trpceski, Michael, Yerbury, Justin J., Ooi, Lezanne
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-04-2019; Springer Nature B.V
• Subjects: 13; 38; 631/378/1689/1285; 631/378/87; 9/74; Aging; Aging - metabolism; Aging - pathology; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - physiopathology; Animal models; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Brain stem; Cell Biology; Cell Culture; Cortical Excitability - drug effects; Cortical Excitability - genetics; Disease Models, Animal; Disease Progression; Embryos; Excitability; Female; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism; Immunology; KCNQ Potassium Channels - genetics; KCNQ Potassium Channels - metabolism; Life Sciences; Male; Membrane Potentials - drug effects; Membrane Potentials - genetics; Membrane Potentials - physiology; Mice; Mice, Transgenic; Motor neuron diseases; Motor neurons; Motor Neurons - drug effects; Motor Neurons - metabolism; Motor Neurons - physiology; Potassium channels (voltage-gated); Spinal cord; Superoxide Dismutase-1 - genetics; Superoxide Dismutase-1 - metabolism
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1538-9

Amyotrophic lateral sclerosis (ALS) is a type of motor neuron disease (MND) in which humans lose motor functions due to progressive loss of motoneurons in the cortex, brainstem, and spinal cord. In patients and in animal models of MND it has been observed that there is a change in the properties of motoneurons, termed neuronal hyperexcitability, which is an exaggerated response of the neurons to a stimulus. Previous studies suggested neuronal excitability is one of the leading causes for neuronal loss, however the factors that instigate excitability in neurons over the course of disease onset and progression are not well understood, as these studies have looked mainly at embryonic or early postnatal stages (pre-symptomatic). As hyperexcitability is not a static phenomenon, the aim of this study was to assess the overall excitability of upper motoneurons during disease progression, specifically focusing on their oscillatory behavior and capabilities to fire repetitively. Our results suggest that increases in the intrinsic excitability of motoneurons are a global phenomenon of aging, however the cellular mechanisms that underlie this hyperexcitability are distinct in SOD1
G93A
ALS mice compared with wild-type controls. The ionic mechanism driving increased excitability involves alterations of the expression levels of
HCN
and
KCNQ
channel genes leading to a complex dynamic of H-current and M-current activation. Moreover, we show a negative correlation between the disease onset and disease progression, which correlates with a decrease in the expression level of
HCN
and
KCNQ
channels. These findings provide a potential explanation for the increased vulnerability of motoneurons to ALS with aging.