PhD: Léa Milan

Physiopathology of the amyotrophic lateral sclerosis : implication of the neuromodulatory systems in the spinal motor netwoks

Defended on December 10, 2014

Abstract

Neuromodulatory systems play a crucial role in the establishment and regulation of spinal motor networks to finely adjust the locomotor rhythm and pattern to the internal and external constraints. It is now well admitted that alterations in neuromodulatory functions are involved in diverse neurologic disorders. Amyotrophic lateral sclerosis is a neurodegenerative disease characterized by the specific loss of cortical and spinal motor neurons. A growing body of evidence now suggests that although ALS syndromes occur in adulthood, alterations can be detected as early as at the embryonic stages in the spinal cord of the rodent model of ALS, the SOD1 mouse.

In this context, we hypothesized that early alterations in the spinal neuromodulatory systems may be involved in the pathophysiology of ALS. To answer this question, in a first step, we compared the monoaminergic modulation of spinal network by recording extracellularly the fictive locomotion produced in the in vitro spinal cord preparation form newborn wild-type and SOD1 mice.
By combining extra- intracellular recordings with immunohistochemical and cellular biology technics, we aimed, in a second step, to investigate the cholinergic synapses arising onto motoneurons and their neuronal source, the lamina X interneurons as a function of the mouse age. Finally, we initiated (1) an innovative behavioural study of mouse motor habits and (2) an analysis of the synaptic plasticity of glutamatergic synapses imping on motoneurons in culture. Altogether, our data demonstrated early and progressive changes of the major spinal neuromodulatory systems: cholinergic, dopaminergic and noradrenergic.

Our data show for the first time that: (1) M2 receptors undergo a complex dynamic under C-bouton that is completely disturbed in SOD1 motoneurons and (2) motoneurons are not the only cellular subtype to degenerate in SOD1 mice. Indeed, we found evidence that neurodegenerative processes also target lamina X cholinergic interneurons in the SOD1 spinal cord.

Keywords : SLA, neuromodulation, spinal cord, transgenic mice, locomotor networks

 

 

Publications

– Léa Milan; Grégory Barrière; Philippe De Deurwaerdère; Jean-René Cazalets and Sandrine S. Bertrand (2014) Monoaminergic control of spinal locomotor networks in SOD1G93A newborn mice. Frontiers in Neural circuits.

– Léa Milan, Gilles Courtand, Laura Cardoit, Frédérique Masmejean, Jean-René Cazalets, Maurice Garret and Sandrine S Bertrand. Age-related changes in pre- and postsynaptic partners of the cholinergic C-boutons apposed to wild-type and SOD1G93A lumbar motoneurons. (soumis).

– Catecholamine/Serotonin Interactions : Systems Thinking for Brain Function and disease. Julie G. Hensler, Francesc Artigas, Analia Bortolozzi, Lynette C. Daws, Philippe De Deurwaerdère, Léa Milan, Sylvia Navailles and Wouter Koek. 2013 (2013) Advances in Pharmacology.

– Sylvia Navailles, Léa Milan, Hanane Khalki, Giuseppe Di Giovanni, Mélanie Lagière, Philippe De Deurwaerdère. Noradrenergic fibers model L-DOPA-derived extracellular dopamine in a region-dependent manner in parkinsonian rats (2014) CNS Neurosciences & Therapeutics.

Committee

  • Pascal Branchereau
    PU Univ Bordeaux  –
    Président
  • Florence Perrin
    Pr, Univ Montpellier 2  –
    Rapportrice
  • Jacques Durand
    CR, Univ Aix-Marseille  –
    Rapporteur
  • Gillian Butler-Browne
    DR, Université Paris 6  –
    Examinatrice
  • Frédéric Brocard
    CR, Univ Aix-Marseille  –
    Examinateur
  • Sandrine Bertrand
    CR, Univ Bordeaux  –
    PhD supervisor

PhD supervisor

Sandrine Bertrand
Chargé de recherche – PhD
CNRS
Team: Coordinations and Plasticities of Spinal Generators
Domain: Motor Systems / Motor Neuron / Spinal Neural Networks

Last update: 10 December 2014