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Séminaire impromptu - Jean-Claude LacailleSELECTIVE REGULATION OF PROTEIN SYNTHESIS AND SYNAPTIC FUNCTION IN MEMORY AND AUTISM

Abstract :


Autism Spectrum Disorders (ASD) encompass a wide spectrum of neuro-developmental diseases that are defined by deficits or unusual behaviors within three domains: social interactions, communication, and repetitive or restricted interests and behaviors. A significant proportion of ASD risk genes encode synaptic proteins. Dysregulation of the molecular machinery controlling translation has been postulated to cause ASD, mainly through increased levels of synaptic proteins and connectivity. The mammalian target of rapamycin (mTOR) is strongly implicated in ASD by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. We show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2) — an eIF4E repressor downstream of mTOR — or eIF4E overexpression lead to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASD. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.

Une invitation de Sandrine Bertrand (INCIA)

Sandrine Bertrand (sandrine.bertrand @ u-bordeaux2.fr)