BDNF and the Restoration of Synaptic Plasticity in Fragile X and Autism

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In animal models of human cognitive impairment there are disturbances in activity-induced remodeling of the dendritic spine actin cytoskeleton and processes of long term potentiation (LTP) that depend upon it. Our program has shown that Brain-derived neurotrophic factor (BDNF) can rescue both processes in several models. This suggests that spine actin remodeling is a final common path impacted in various conditions of cognitive dysfunction and that, through effects on this process, BDNF can offset cognitive deficits. Project 1 will test this for the Fmr1-KO mouse model of Fragile-X Syndrome (FXS) (a mental retardation syndrome with susceptibility for autism). The Fmr1-KOs have abnormal LTP threshold and stabilization. We find they also lack of normal activity-induced Rac GTPase > p21 activated kinase (PAK) signaling proposed to mediate F-actin and LTP stabilization, but BDNF infusion can still stabilize potentiation in the mutants. Proposed studies will use acute hippocampal slices and in vivo preparations to understand deficiencies in F-actin regulation, and to test an ampakine-BDNF strategy for restoration of function in Fmr1-KOs. Aim 1 will test if failed Rac activation accounts for signaling and LTP impairments in the KOs and if this is secondary to changes in synaptic integrin function. Aim 2 will test if BDNF infusion restores spine signaling through PAK or drives other systems to effect stabilization of spine F-actin and LTP in the KOs. Aim 3 will then test if in vivo treatments (ampakine or ampakine+MPEP) that increase BDNF protein content similarly restore actin regulation and LTP as assessed ex-vivo. Aim 4 will use an unsupervised learning paradigm to test if upregulating BDNF leads to heightened signaling through BDNF's TrkB receptor and a normalization of exploratory behavior and learning in the mutants; these studies will also test if the topography of synapse activation is abnormal in the mutants and normalized in association with increases in BDNF signaling. Finally, Aim 5 will test if TBS-induced LTP, and steps in actin signaling that are perturbed in the Fmr1-KO mice, are disturbed in other animal models of autistic phenotype and corrected by BDNF: this work will evaluate effects in the BTBR T[+] tf/J mice and Tuberous Sclerosis complex model mice. Together these studies will identify mechanisms underlying deficits in LTP stabilization in FXS model mice, determine if the same processes are disturbed in other mouse strains with features of autism, and test if increasing endogenous BDNF is an effective therapeutic strategy for correcting impairments in the cellular mechanisms of learning and memory in models of cognitive conditions associated with autism.