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Reversing Synaptic Dysfunction and Aberrant Behavior in Mouse Models of Autism Spectrum Disorder

Saturday, 4 May 2013: 11:30
Auditorium (Kursaal Centre)
E. Klann, Center for Neural Science, New York University, New York, NY
Background:   A requirement for de novo protein synthesis is one of the hallmarks of long-lasting synaptic plasticity and long-term memory. An increasing number of studies, including several from our laboratory, have identified signaling cascades, including the mTORC1 signaling pathway, that couple neurotransmitter and neurotrophin receptors to the translation regulatory machinery during the formation of long-lasting synaptic plasticity and the consolidation of long-term memory. Interestingly, mutations in negative upstream regulators and downstream effectors of mTORC1, including fragile X mental retardation protein (FMRP) and the eukaryotic initiation factor 4E (eIF4E) are associated with several types of developmental disability and autism spectrum disorder (ASD).

Objectives: Our objective is to determine whether exaggerated protein synthesis is a causative factor for synaptic dysfunction and aberrant behavior in mouse models of ASD, including fragile X syndrome (FXS) model mice and transgenic mice that overexpress eIF4E.

Methods: FXS model mice and eIF4E transgenic (eIF4E Tg) mice were examined for exaggerated protein synthesis and altered translational control. First, we identified the altered translational control mechanisms in the brains of FXS and eIF4E Tg mice. Then we utilized genetic and pharmacological approaches to target the translational control molecules of interest, including eukaryotic initiation factor 4F (eIF4F) and p70 S6 kinase 1 (S6K1).

Results: We found that genetic reduction of S6K1 in FXS model mice corrected exaggerated protein synthesis, abnormal synaptic plasticity, and multiple aberrant behaviors. We currently are determining whether treating FXS model mice with an inhibitor of S6K1 can reverse the aforementioned phenotypes. In addition, we have found that compounds that target eIF4F can reverse exaggerated protein synthesis and synaptic dysfunction in eIF4E Tg mice. Moreover, the eIF4F inhibitors reverse ASD-associated behaviors displayed by eIF4E Tg mice, including repetitive behaviors, behavioral inflexibility, and abnormal social behavior. We currently are determining whether the compounds that target eIF4F have similar effects on aberrant behaviors displayed by FXS model mice.

Conclusions: Our studies strongly suggest that exaggerated protein synthesis in mice triggers synaptic dysfunction and aberrant behaviors that are associated with ASD. These studies have revealed important links between abnormal translational control and synaptic dysfunction, as well as behaviors associated with ASD. Finally, these studies have provided insight into the molecular basis of certain types of developmental disability and ASD, and have identified a novel class of targets for the development of therapeutics for the treatment of individuals with ASD.

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