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.
This project will test if mice with autistic behavioral traits have impairments to the same biological mechanisms underlying learning and memory, as occur in other syndromes of cognitive dysfunction and if well-tolerated drugs causing the brain to increase production of Brain derived neurotrophic factor can normalize these biological mechanisms and behavior in these animals. This includes tests to determine if the drugs correct behavioral abnormalities in the mouse model of Fragile X mental retardation syndrome.
|Wang, Yubin; Hall, Randy A; Lee, Moses et al. (2017) The tyrosine phosphatase PTPN13/FAP-1 links calpain-2, TBI and tau tyrosine phosphorylation. Sci Rep 7:11771|
|Zhu, Guoqi; Briz, Victor; Seinfeld, Jeff et al. (2017) Calpain-1 deletion impairs mGluR-dependent LTD and fear memory extinction. Sci Rep 7:42788|
|Wang, W; Cox, B M; Jia, Y et al. (2017) Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. Mol Psychiatry :|
|Cox, Conor D; Palmer, Linda C; Pham, Danielle T et al. (2017) Experiential learning in rodents: past experience enables rapid learning and localized encoding in hippocampus. Learn Mem 24:569-579|
|Seinfeld, Jeff; Baudry, Neema; Xu, Xiaobo et al. (2016) Differential Activation of Calpain-1 and Calpain-2 following Kainate-Induced Seizure Activity in Rats and Mice. eNeuro 3:|
|Chen, Yuncai; Molet, Jenny; Lauterborn, Julie C et al. (2016) Converging, Synergistic Actions of Multiple Stress Hormones Mediate Enduring Memory Impairments after Acute Simultaneous Stresses. J Neurosci 36:11295-11307|
|Wang, Yubin; Hersheson, Joshua; Lopez, Dulce et al. (2016) Defects in the CAPN1 Gene Result in Alterations in Cerebellar Development and Cerebellar Ataxia in Mice and Humans. Cell Rep 16:79-91|
|Wang, Yubin; Lopez, Dulce; Davey, Pinakin Gunvant et al. (2016) Calpain-1 and calpain-2 play opposite roles in retinal ganglion cell degeneration induced by retinal ischemia/reperfusion injury. Neurobiol Dis 93:121-8|
|Sun, Jiandong; Liu, Yan; Tran, Jennifer et al. (2016) mTORC1-S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice. Cell Mol Life Sci 73:4303-4314|
|Liu, Yan; Wang, Yubin; Zhu, Guoqi et al. (2016) A calpain-2 selective inhibitor enhances learning & memory by prolonging ERK activation. Neuropharmacology 105:471-477|
Showing the most recent 10 out of 98 publications