P3M

Plasticity and Physio-pathology of rhythmics Motor networks

We study the functional organization of neural circuits in the spinal cord both in development and in pathological conditions (i.e. spinal cord injury (SCI)). We are interested in the mechanisms by which neurons and neural networks operate to generate movements. We use rodents (rats and mice) as a model system to understand the development and the organization of the spinal motor networks at a molecular, cellular and integrative level. The lab is also engaged in characterizing plasticity in motoneurons following lesions of the spinal cord and in devising target treatments of dysfunctional motor symptoms in humans.

Despite many years of studies, the basic organization of the mammalian locomotor central pattern generator (CPG) remains poorly understood. In traditional schemes, pacemakers have been assigned a subservient function for the locomotion. Our discovery of a new INaP-dependent bursting interneurons challenges this view and makes the pacemaker hypothesis a valuable model to account for the locomotor rhythm. We further show that developmental transitions in motor behavior may be linked to the emergence of a unique thermosensitive plateau properties in motoneurons during early life. Thus, we are ahead of new concepts where bistable cells are functionally integrated to the locomotor network. Unravelling the functional operation of the locomotor network and linking bistable properties to specific behavioral outcomes is one the challenge of the team.

We are also examining how locomotor network organization and functional properties change below the spinal cord lesion. Most of therapies for motor deficits following SCI are usually ineffective because pathophysiological mechanisms of the sublesional spinal cord leading to an excitatory/inhibitory imbalance remain unknown. One of the other exciting challenge of the team relies on identifying the upstream mechanisms of the pathophysiology of spasticity to develop effective, tolerable and minimally invasive treatment.

We use a broad technical approach involving electrophysiology, biochemistry, imaging, anatomy, optogenetics and genetics to address three major questions:

What are the mechanisms underlying the pacemaker activities of the rythmogenic locomotor network ?

The hindlimb locomotor Central Pattern Generator (CPG), located in the lumbar spinal cord, generates coordinated rhythmic activity on motoneurons that drives locomotor movements. Our investigations pave the way for a new working hypothesis in which INaP-dependent pacemaker neurons play a key role in the locomotor rhythm generation. The ultimate goal will be to validate and refine the model in a series of complementary experimental studies performed in neonatal rodents, and aiming to identify the location, the modulation and the maturation of pacemakers.

How does the plateau properties emerge in motoneurons ?

We demonstrated that motoneurons innervating an extensor muscle of the ankle exhibit thermosensitive plateaus well before the rats start to execute a weight-bearing locomotion. We also showed that motoneurons behave as a four-stroke engine such as the INaP-dependent spiking activity (step 1) triggers Ca2+ entry through voltage-gated Ca2+ channels (step 2) which initiates a Ca2+-induced Ca2+-released process (step 3) that ultimately activates a thermosensitive non-selective cationic current (ICaN) to promote plateaus (step 4). We identified Nav1.6 channels responsible for INaP and L-calcium channels for Ca2+ entry, but the identity of channels at the source of ICaN remain to be established.

Because ICAN initiates activity-dependent changes to intrinsic excitability, we also examine whether the plasticity of the locomotor behavior is associated with some changes from ICAN in lumbar motoneurons and/or in pacemakers of the locomotor CPG in response to a sensorimotor-restriction.

What are the anatomical and functional mechanisms underlying spasticity after SCI and how to transfer our findings into clinical applications at the bedside ?

Spasticity results from excess motoneuron excitation due to a concomitant upregulation of INaP with a disinhibition. We revealed the causal relationship between calpain (a protease) and the increase of INaP after SCI. It is worth mentioning that KCC2 in dorsal horn neurons has been reported to be sensitive to calpains after a peripheral nerve injury, which alters the co-transporter ability to extrude Cl- ions thereby reducing the inhibition. This led us to consider the exciting possibility that a proteolytic cleavage of both Na+ channels and KCC2 by calpains may compose the upstream mechanism of the excitatory/inhibitory imbalance of motoneurons at the origin of spasticity after SCI. One of the strategies employed in the lab to counteract this excitatory/inhibitory imbalance is training (passive exercise of the hindlimbs) combined with a pharmacological treatment which boosts the serotoninergic system.

An important aspect of this aim is to transfer our findings into clinical applications at the bedside. The current authorized therapeutic arsenal consists mainly in the administration of baclofen, tizanidine or local BTX-A with relative efficacy. Therefore, the need to expand opportunities to identify an effective treatment is a clinical reality. However, the development of new therapies is an arduous, time-consuming and costly task. Repurposing drugs, already established as safety in humans, is gaining attraction because of its potential to overcome a drug development process.


Collaborations

National

- Christian Gestreau, Aix Marseille Université (AMU). Role of KCNK5 channels in audition.
- Pierre Launay, Université Paris Descartes. Contribution of TRPM4 channels in motor control.
- Aziz Moqrich, Insitut de Biologie du Developpement de Marseille Luminy. Contribution of TRPV1/3 in motor control.
- Pascal Salin, Insitut de Biologie du Developpement de Marseille Luminy (UMR 7288, AMU)
- Monique Esclapez, Institut de Neurosciences des systèmes (UMR 1106, AMU).
- Laure Rondi-Reig, Neurobiologie des Processus adaptatifs (UMR 7102, CNRS-Université Pierre et Marie Curie).
- Françoise Muscatelli, Institut de Neurobiologie de la Méditerranée (UMR 901, Inserm-AMU)
- François Lambert/Muriel Thoby-Brisson, Institut de Neurociences cognitives et intégratives d’Aquitaine (UMR 5287, CNRS-Université Victor Segalen Bordeaux 2).
- P. Gressens/O. Baud, Hôpital Robert-Debré, Paris.
- M-H Canu/B. Bastide, Université de Lille 1 et 2.
- N. Baril/N Turbe-Lorenzo, Fédération 3C, AMU-CNRS, Marseille.

International

- Ron Harris Warrick, Cornel University, USA. Motoneuron bistable properties.
- Balazs Rozsa, Two-photon imaging center, Hungarian Academy of sciences. Budapest, Hungary. Motoneuronal Calcium response.
- GlaxoSmithKline R&D, United Kingdom. Nav 1.6 Proteolitic mechanisms after spinal cord injury.
- Uwe Heinemann, Institut of Neurophysiology, Charité-Universitätsmedizin Berlin, Germany. Extracellular ionic changes in the locomotor system.
- Tom Ruigrok, Erasmus MC Rotterdam (The Netherland)
- Joel Glover, University of Oslo (Norway)
- Jan Marino Ramirez, Seattle Children hospital, USA.
- F. Barbe/V. Massicotte, Temple school of medicine, Philadelphia, USA.
- M Delcour/N. Dancause, Department of Neuroscience. Uniersity of Montréal, Canada.
- M. Tsuji/M.Ohshima/Y. Hattori, Department of Stroke and cerebrovascular diseases, Osaka, Japan.

Alumni

- Pflieger Jean-Francois (Post-doctoral researcher 2002-2004, currently Associate professor at University of Montreal, CA).
- Ben Mabrouk Faiza (PhD student 2003-2007, currently Research Associate at Newcastle University, UK).
- Jean-Xavier Céline (PhD student 2003-2008, currently Research Associate at Hotchkiss Brain Institute, University of Calgary, CA).
- Tazerart Sabrina (PhD student 2006-2010, currently Post-doctoral researcher at University of Montreal, CA).
- Stil Aurélie (PhD student 2007-2011, currently Post-doctoral researcher at University of Montreal, CA).
- Sadlaoud Karina (PhD student 2008-2012, currently business manager, Marseille, FR).
- Bos Rémi (PhD student 2009-2012, currently Post-doctoral researcher at University of Aix-Marseille, FR).
- Gackière Florian (Post-doctoral researcher 2011-2014, MEA Engineer at Neuroservice lab, Aix-en-Provence, FR)
- Bouhadfane Mouloud (PhD student 2011-2014, currently student at medical school of Aix-Marseille University, FR).
- Khalki Loubna (Post-doctoral researcher 2012-2014, currently Associate professor at University of Casablanca, MA).
- Mancuso Renzo (Post-doctoral researcher 2014-2015, currently Post-doctoral researcher at Centre for Biological Sciences at the University of Southampton, UK).
- Zanella Sébastien (Post-doctoral researcher 2014-2016, currently lecturer at Aix-Marseille Academia, FR)
- Plantier Vanessa ((PhD student 2012-2015, currently Post-doctoral researcher at INMED, Marseille, FR).

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