Periodic Reporting for period 2 - ADELE (Early defects in the dynamic of the spinal sensorimotor network: is ALS a post-natal neurodevelopmental disorder ?)
Reporting period: 2021-04-01 to 2022-03-31
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.
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.
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.