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La mouche comme mode'le pour étudier les effets neurotoxiques du glutamate chez l'homme

April 06, 2004

La drosophile (ou mouche du vinaigre) peut servir de mode'le pour comprendre le rôle des neurotransmetteurs excitateurs comme le glutamate dans les dommages subis par le cerveau humain lors d'accidents vasculaires et dans certaines maladies neurodégénératives. C'est ce que vient de montrer une équipe du CNRS dirigée par Serge Birman, '� l'Institut de biologie du développement de Marseille (1). Ces affections du syste'me nerveux seraient souvent induites ou aggravées par la libération massive et l'accumulation du glutamate dans l'espace extracellulaire, entra'®nant la mort des neurones, un effet appelé � excitotoxicité �. Cette accumulation du glutamate peut '™tre reproduite chez la mouche o'� elle provoque une dégénérescence de certaines structures du cerveau et des modifications du comportement. La démonstration des effets neurotoxiques de l'accumulation du glutamate chez la drosophile ouvre la voie '� l'étude génétique des effets nocifs de ce neurotransmetteur sur le cerveau humain.

Le glutamate, un acide aminé communément utilisé dans l'industrie alimentaire comme exhausteur de go'�t, et connu des neurobiologistes comme le neurotransmetteur excitateur majeur du cerveau humain, est également un neurotoxique puissant. Chez l'homme, lors d'accidents vasculaires cérébraux, la libération massive de glutamate par les cellules en manque d'oxyge'ne semble jouer un rôle direct dans la perte des neurones et l'extension des lésions dans les jours suivant le traumatisme initial. Les effets déléte'res du glutamate pourraient également '™tre impliqués dans la progression de certaines maladies neurodégénératives comme la maladie de Huntington et la sclérose latérale amyotrophique (SLA).

Le glutamate libéré est normalement recapturé dans les cellules nerveuses gr'�ce '� des protéines transporteurs, qui maintiennent les taux de ce neurotransmetteur sous le seuil de toxicité. En inactivant le seul transporteur du glutamate connu chez la drosophile, Serge Birman et son équipe ont pu observer les effets de l'accumulation du glutamate dans le cerveau de cet insecte. Les mouches ainsi traitées présentent des anomalies caractéristiques du comportement. Elles sont léthargiques et ne cherchent pas '� échapper '� la main de l'expérimentateur, mais paradoxalement réagissent de fa'�on exacerbée '� un choc. Ces effets sont partiellement réversibles par l'expression chez ces mouches d'un transporteur du glutamate humain ou l'administration dans leur nourriture d'agents pharmacologiques protecteurs des neurones. L'accumulation du glutamate entra'®ne également une augmentation du stress oxydatif dans les cellules et une dégénérescence marquée de la région du cerveau des insectes contenant les prolongements neuronaux et les contacts synaptiques. Les effets observés chez la mouche sugge'rent que le glutamate présente la m'™me toxicité dans le cerveau des insectes que chez les mammife'res et l'homme. Les drosophiles sans transporteur du glutamate constituent un syste'me mode'le plus aisé '� manipuler que les souris habituellement utilisées pour ce type d'étude. Ces travaux devraient donc permettre des progre's décisifs dans la compréhension des mécanismes moléculaires de la neurotoxicité du glutamate et du rôle de ce neurotransmetteur excitateur dans les dégénérescences cérébrales chez l'homme.

Référence :
Decreasing glutamate buffering capacity triggers oxidative stress and neuropil degeneration in the Drosophila brain. Thomas Rival, Laurent Soustelle, Colette Strambi, Marie-Thére'se Besson, Magali Iché et Serge Birman. Current Biology, 2004. 14 : 1-20.

1 : Laboratoire de Génétique et Physiologie du développement, CNRS-Inserm-Université de la Méditerranée, Campus de Luminy, Marseille.

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