Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency
In: ISSN: 1946-6234, 2024
academicJournal
Zugriff:
International audience ; 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 Sod1 G86R and Fus Δ NLS/+ 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 SOD1 G93A and Fus Δ NLS/+ 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.
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Cortical hyperexcitability in mouse models and patients with amyotrophic lateral sclerosis is linked to noradrenaline deficiency
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Autor/in / Beteiligte Person: | Scekic-Zahirovic, Jelena ; Benetton, Cristina ; Brunet, Aurore ; Ye, Xiaoqian ; Logunov, Evgeny ; Douchamps, Vincent ; Megat, Salim ; Andry, Virginie ; Kan, Vanessa Wing Yin ; Stuart-Lopez, Geoffrey ; Gilet, Johan ; Guillot, Simon ; Dirrig-Grosch, Sylvie ; Gorin, Charlotte ; Trombini, Margaux ; Dieterle, Stéphane ; Sinniger, Jérôme ; Fischer, Mathieu ; René, Frédérique ; Gunes, Zeynep ; Kessler, Pascal ; Dupuis, Luc ; Pradat, Pierre-François ; Goumon, Yannick ; Goutagny, Romain ; Marchand-Pauvert, Véronique ; Liebscher, Sabine ; Rouaux, Caroline ; Neuroscience et Psychiatrie Translationnelle de Strasbourg (STEP) ; Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM) ; Centre de Recherche en Biomédecine de Strasbourg (CRBS) ; Laboratoire d'Imagerie Biomédicale Paris (LIB) ; Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS) ; Ludwig Maximilian University Munich = Ludwig Maximilians Universität München (LMU) ; Laboratoire de neurosciences cognitives et adaptatives (LNCA) ; Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS) ; Plateau technique de Spectrométrie de Masse (SM-INCI / CNRS UPR3212) ; Institut des Neurosciences Cellulaires et Intégratives (INCI) ; Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS) ; CHU Pitié-Salpêtrière AP-HP ; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU) ; Munich Cluster for systems neurology Munich (SyNergy) ; Technische Universität Munchen - Technical University Munich - Université Technique de Munich (TUM)-Ludwig Maximilian University Munich = Ludwig Maximilians Universität München (LMU) ; University Hospital of Cologne Cologne ; AMF-Téléthon, ARSLA, Emmy Noether Program of the German Research Foundation, Cluster for Systems Neurology, CSC, France DFT, Fondation ARSEP,Fondation Vaincre Alzheimer, France Parkinson, German Research Foundation under Germany’s Excellence Strategy within the framework of the Munich ; ANR-21-CE37-0033,FrequALS,Altération du couplage inter-fréquence cortical dans la sclérose latérale amyotrophique en tant que biomarqueur et cible thérapeutique potentiels(2021) ; European Project: 639737,H2020,ERC-2014-STG,CorticALS(2015) |
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Zeitschrift: | ISSN: 1946-6234, 2024 |
Veröffentlichung: | HAL CCSD ; American Association for the Advancement of Science (AAAS), 2024 |
Medientyp: | academicJournal |
DOI: | 10.1126/scitranslmed.adg3665 |
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