Fragile X Syndrome (FXS) is a disorder caused by impaired expression of fmr1 that results in cognitive impairments as well as behavioral and physical characteristics. Previous research using mouse models of FXS with deleted Fmr1 has shown deficits in synaptic plasticity in the dentate gyrus that are accompanied by deficits in dentate gyrus associated learning tasks. This proposal will test the hypothesis that glycogen synthase kinase-3 (GSK3), an enzyme with pathologically increased activity in Fmr1-/- mice, contributes to synaptic and cognitive deficits associated with the dentate gyrus. Specifically, using electrophysiological techniques I will determine whether hyperactive GSK3 causes deficits in NMDAR dependent long-term potentiation (LTP) and long-term depression (LTD), two forms of plasticity thought to underlie learning and memory. I also hypothesize that hyperactive GSK3 causes decreased learning in Fmr1-/- mice. I will assess learning using rodent behavioral assays. While elucidating the role of hyperactive GSK3 in FXS, I will also seek to identify downstream targets of GSK3 that are dysregulated in Fmr1-/- mice. Data obtained from this proposal will bolster previous studies suggesting GSK3 as a therapeutic target in the treatment of Fragile X Syndrome as well as identify novel therapeutic targets downstream of GSK3 signaling.
Fragile X Syndrome is the most common inherited form of mental retardation and the leading known genetic cause of autism. Attempts to understand the underlying pathophysiology of this disorder seek to identify novel therapeutic strategies in treating both Fragile X Syndrome and autism.
|Franklin, Aimee V; Rusche, James R; McMahon, Lori L (2014) Increased long-term potentiation at medial-perforant path-dentate granule cell synapses induced by selective inhibition of histone deacetylase 3 requires Fragile X mental retardation protein. Neurobiol Learn Mem 114:193-7|
|Franklin, Aimee V; King, Margaret K; Palomo, Valle et al. (2014) Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in fragile X mice. Biol Psychiatry 75:198-206|