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Impaired translational regulation of brain development in autism spectrum disorders

Principal Investigator:
  • Jelena Popic, McGill University
  • Azrieli Foundation
  • McGill University

Project Overview

Autism spectrum disorders (ASDs) are a group of complex neurodevelopmental disorders with distinguished early emerging behavioral disruptions (speech impairments, social communication, repetitive behaviors) and a rising rate of diagnosis to an estimated 1 in 68 children. Synaptogenesis occurs in the vertebrate central nervous system from early embryonic life to adulthood. Proper assembly of neural circuits during synaptogenesis depends on the balance between excitatory and inhibitory (E/I) inputs. Disruption of this balance can lead to neurodevelopmental disorders such as autism, epilepsy, Rett syndrome or Fragile X syndrome. Gamma-aminobutyric acid (GABA) is a main inhibitory neurotransmitter in the brain, but during early development, GABAergic currents are mainly excitatory. The shift from excitatory to inhibitory actions of GABA occurs between the first two postnatal weeks in rodents due to the reduction of intracellular chloride concentration which is mediated by a decrease in the expression of the main chloride importer, NKCC1, and an increase in the main chloride exporter, KCC2. Protein synthesis (mRNA translation) is an essential process in all organisms. Eukaryotic translation initiation factor 4E (eIF4E) is the least abundant translation-initiation factor, and its activity is rate-limiting and tightly regulated. 4E-BP2 is the major eIF4E-binding protein which acts as a translational suppressor. It has an important role in long-lasting synaptic plasticity, learning, and memory. Dysregulation of chloride homeostasis and a delay in the shift of GABAergic transmission during synaptogenesis in BP2KO mice could be the cause of the ASD-like phenotype observed in these mice. Therefore, normalization of the increased NKCC1/KCC2 ratio using bumetanide, in order to reverse ASD-like phenotypes, could provide an important insight into the developmental mechanisms of translational control in ASD and might lead to a new pharmaco-therapeutical direction for the prevention of behavioral impairments in ASD.