Grant: Fellowship Award - Priority Announcement: Fragile X (SHOPP)

Fragile-X syndrome (FXS) is the most common form of inherited intellectual disability and can be considered as the best characterized form of autism spectrum disorder. The disorder is caused by repressed transcription of the gene Fmr1 which codes for the Fragile-X Mental Retardation Protein (FXMR). Our preliminary results have shown that FMRP have interaction at the synapse in the dentate gyrus (DG) of the hippocampus (brain region for learning and memory). An alteration in the ratio of AMPA receptor to NMDA receptor in the DG was found in the Fmr1 knock-out mice. We have shown clear and robust impairments in NMDA receptor-dependent long-term potentiation and long-term depression (a form of learning and memory formation) in the DG of adult male Fmr knock-out mice. We also found that Fmr KO mice showed a learning impairment on context discrimination, a learning task that is also impaired in animals that lack functional NMDA receptors in the DG. Others also report that FMRP is regulated by brain-derived neurotrophin factor that influences neuronal survival and maturation and regulates synaptic plasticity. Since DG is a site of specific impairment in FXS, we aim to evaluate the role of DG in the pathophysiology of FXS and how FXS regulate synaptic plasticity in DG. Using well established Fmr KO mice, we will examine if there are physiological or morphological deficits in DG and alterations in behaviours that are DG dependent. We also examine the relative importance of the DG to cognitive impairment using DG-specific Fmr KO and DG-specific Fmr knock-in mice. In addition, we aim to determine how FMRP alters the BDNF signaling pathway in the DG, which may in turn affect the functions of NMDA receptor in synaptic plasticity. This work will be critical for determining the linkage between Fmr1 expression and specific form of learning and memory and will unmask how Fmr1 gene products are involved in structural and functional processes in the mammalian brain