Early defects in the dynamic of the spinal sensorimotor network: is ALS a post-natal neurodevelopmental disorder ?

Informations projet

ADELE

N° de convention de subvention: 882779

DOI

10.3030/882779

Projet clôturé

Date de signature de la CE 26 Mars 2020

Date de début 1 Avril 2020

Date de fin 31 Mars 2022

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 190 676,16

Contribution de l’UE

€ 190 676,16

Coordonné par

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 2 - ADELE (Early defects in the dynamic of the spinal sensorimotor network: is ALS a post-natal neurodevelopmental disorder ?)

Période du rapport: 2021-04-01 au 2022-03-31

Résumé du contexte et des objectifs généraux du projet

Amyotrophic lateral sclerosis (ALS) is a progressively paralyzing neurodegenerative disorder usually fatal within 3 years of diagnosis. ALS affects motoneurons located in the motor cortex, brainstem and spinal cord. The incidence of ALS ranges between 2-3 per 100 000 person-years, with a median age of age comprised between 50 and 70 years. The majority of cases being diagnosed are considered sporadic, while approximately 10% of patients have a familial history of the disease. ALS causing mutations in Cu-Zn superoxide dismutase (SOD1) were the first to be identified and are among the most frequently found in familial cases. Transgenic mice that express ALS-causing mutations in SOD1 recapitulate the main traits of the human disease and represent therefore a reliable and informative model to comprehend pathogenic mechanisms.
The vast majority of ALS research has legitimately approached this disorder as an adult condition. The concept that this disease can take root very early in the life of patients has received little consideration, while structural and fundamental sensorimotor functions are established during specific developmental window. Indeed, this critical period of spinal network organization being detrimental throughout the lifespan. Surprisingly, apprehending ALS as a developmental disease of sensorimotor network connectivity is a major conceptual step, both at the level of our vision to understand pathogenic mechanisms and especially at the therapeutic scale. Considering an early, infantile origin, sub-lethal aberrant network connectivity, escaping the vigilance of parents and clinicians, will provide new insight into ALS aetiology and open innovative therapeutic perspective.
This MSCA aims to identify alterations in early spontaneous sensory-evoked electrical activities in the spinal cord and motor reflexes of neonatal ALS animals to propose innovative therapeutic intervention.
A strong collaboration and a successful transfer of knowledge and know-how enable to explore physiological and behavioral aspects related to the hypothesis of a developmental origin of ALS. The objectives remain competitive and original, the ADELE consortium offers the possibility to explore these new perspectives to better understand and potentially propose new therapies for this devastating pathology.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

The global health crisis posed by the Coronavirus disease COVID-19 pandemic has considerably slowed down the pace of the project. The arrival of mouse model of ALS in the laboratory has been significantly delayed. In addition, border closure did not facilitate the supply of small equipment required for the project (silicone-based 16 electrode probes…). Nevertheless, this period was fruitful in terms of exchanges and discussions with collaborators from different fields and allowed the writing of two reviews in peer-reviewed international journal (Crabé et al., Cells, 2020; Layalle et al., Int J Mol Sci, 2021) and a book chapter (Scamps et al., Exons Eds, 2021). All these publications acknowledged MSCA funding. Following the lab lock-down, the first months were employed to learn about multi-electrode extracellular recording, local field potential (LFP) and multiunit activity (MUA) recordings, repeating the original experiments performed in the neonatal rats (Inacio et al., Nat Commu, 2016). However, these LFP and MUA recordings are particularly challenging in mouse spinal cord. The physiological barriers encountered in newborn mice, compared to rats, led us to adapt our recording model and develop recording in mouse spinal cord preparations. These offer the advantage of adhering more closely to the 3Rs rule. It also allows to screen drugs more rapidly. During the outgoing phase we worked on the technical aspects of this preparation.
During the incoming phase my objective was to import this knowledge and know-how into the laboratory. We were able to set up a complete recording station only adapted to LFP and MUA recording on spinal cord preparations. Our setup was developed to offer a system perfectly adapted to spinal cords with an ad hoc perfusion system that we designed. This period was prolific in terms of exploration of the literature on the mechanisms of disease propagation with the writing of a review published in Brain Communication (Gosset P, Brain Commun, 2022). An original publication which writing started during the outgoing phase is currently being finalised for submission during 2022. In spite of the important delays that we encountered for the purchase of the recording material or other small equipment, in relation with the sanitary crisis, the incoming phase was a success for the transfer of knowledge and technology.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

This MSCA aims at exploring the spatiotemporal dynamics of spinal network activity during post-natal development of an ALS mouse model. We propose to combine complementary areas of expertise to answer a question that has never been functionally addressed before: is ALS a developmental disease that originates when spinal circuits are first established and remains silent before reaching a clinical breakthrough point? This conceptual paradigm shift requires a scientifically robust proof of concept in order to stimulate new examination protocols aimed to reveal early preclinical markers of the disease raising an alert towards early ALS diagnostics, to guide screening of genetic background in the cohort of patients with a risk of ALS development, and will open large time window for the new treatments preventing the disease. During perinatal development of mouse, motoneurons already exhibits synaptic and excitability defects (Scamps, ALS Exon ed, 2021). However, these defects are not clinically translated. Our results obtained by early reflex behavior indeed testify that at the macroscopic scale, defects of the neuronal circuitry are compensated and allow an adaptation of the animals to the environment.
Currently, no laboratory has been able to study sensory-motor activity in spinal cord neonate mouse using a translaminar extracellular recording approach. This development, as we have experienced, is particularly challenging but still remains a major asset in our understanding of the disease. This interdisciplinary approach implicates electrophysiologists, neurobiologists, physicists and mathematicians to propose an innovative and potentially ground-breaking description of pathophysiological process underlying ALS pathogenesis. Project outcomes would enable detection at very early developmental stages in ALS mice, well before the emergence of clinical symptoms and support novel preventive and effective therapy. Indeed, our goal is to identify very early network defects in order to perform a targeted therapeutic intervention on a short developmental period and to evaluate the benefits in adults. Reconsidering ALS as a neurodevelopmental disease whose effective therapy consists in targeting the early stages remains an original approach that will surely raise many questions but will open new horizons.
This two-year period addressed the behavioral aspects associated with perinatal development. An important gain of knowledge and know-how will allow us with all the partners of this project to perform for the first time LFP and MUA recordings in complete spinal cord preparations of ALS mouse models and to propose a unique and innovative platform for the screening of small molecules with high therapeutic potential.

Ongoing installation of an LFP and MUA recording setup in spinal cord preparations

multielectrode extracellular recordings from neonate mouse spinal cord