Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency.
Fiche publication
Date publication
mars 2024
Journal
Science translational medicine
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GOUMON Yannick
Tous les auteurs :
Scekic-Zahirovic J, Benetton C, Brunet A, Ye X, Logunov E, Douchamps V, Megat S, Andry V, Kan VWY, Stuart-Lopez G, Gilet J, Guillot SJ, Dirrig-Grosch S, Gorin C, Trombini M, Dieterle S, Sinniger J, Fischer M, René F, Gunes Z, Kessler P, Dupuis L, Pradat PF, Goumon Y, Goutagny R, Marchand-Pauvert V, Liebscher S, Rouaux C
Lien Pubmed
Résumé
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the and ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving and mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.
Mots clés
Humans, Mice, Animals, Amyotrophic Lateral Sclerosis, metabolism, Superoxide Dismutase-1, genetics, Neurodegenerative Diseases, metabolism, Spinal Cord, metabolism, Norepinephrine, deficiency, Disease Models, Animal, Mice, Transgenic, Superoxide Dismutase, metabolism, Autonomic Nervous System Diseases, Dopamine beta-Hydroxylase, deficiency
Référence
Sci Transl Med. 2024 03 13;16(738):eadg3665