title: Early functional deficit and microglial disturbances in a mouse model of amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motoneurons degeneration. There is today no clear-cut pathogenesis sequence nor any treatment. However growing evidences are in favor of the involvement, besides neurons, of several partners such as glia and muscles. To better characterize the time course of pathological events in an animal model that recapitulates human ALS symptoms, we investigated functional and cellular characteristics of hSOD1(G93A) mice.
  
  
  RESULTS
  We have evaluated locomotor function of hSOD1(G93A) mice through dynamic walking patterns and spontaneous motor activity analysis. We detected early functional deficits that redefine symptoms onset at 60 days of age, i.e. 20 days earlier than previously described. Moreover, sequential combination of these approaches allows monitoring of motor activity up to disease end stage. To tentatively correlate early functional deficit with cellular alterations we have used flow cytometry and immunohistochemistry approaches to characterize neuromuscular junctions, astrocytes and microglia. We show that (1) decrease in neuromuscular junction's number correlates with motor impairment, (2) astrocytes number is not altered at pre- and early-symptomatic ages but intraspinal repartition is modified at symptoms onset, and (3) microglia modifications precede disease onset. At pre-symptomatic age, we show a decrease in microglia number whereas at onset of the disease two distinct microglia sub-populations emerge.
  
  
  CONCLUSIONS
  In conclusion, precise motor analysis updates the onset of the disease in hSOD1(G93A) mice and allows locomotor monitoring until the end stage of the disease. Early functional deficits coincide with alterations of neuromuscular junctions. Importantly, we identify different sets of changes in microglia before disease onset as well as at early-symptomatic stage. This finding not only brings a new sequence of cellular events in the natural history of the disease, but it may also provide clues in the search for biomarkers of the disease, and potential therapeutic targets.
authors.affiliation: INSERM U1051, Institute for Neurosciences of Montpellier, Pathophysiology and Therapy of Sensory and Motor Deficits, Saint Elio Hospital, Montpellier, France.
authors.forename: Yannick Nicolas
authors.initials: YN
authors.lastname: Gerber
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Sabourin
authors.forename: Miriam
authors.initials: M
authors.lastname: Rabano
authors.forename: Maria d M
authors.initials: Md
authors.lastname: Vivanco
authors.forename: Florence Evelyne
authors.initials: FE
authors.lastname: Perrin
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology* / Q000503:physiopathology*; D000818:Animals; D001253:Astrocytes / Q000473:pathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology*; D009043:Motor Activity / Q000502:physiology; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000473:pathology / Q000503:physiopathology; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics; D013997:Time Factors
chemical_list: D013482:Superoxide Dismutase