Memory and cognitive disorders are associated with abnormal dendritic spines and/or disturbances to signaling regulating the spine actin cytoskeleton. Complementary results show that long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory encoding, requires spine actin remodeling. These observations suggest the hypothesis that defects in the cytoskeletal mechanisms of LTP consolidation represent a shared neurobiological basis for memory disturbances, and a therapeutic target for improving cognitive performance, in a variety of conditions. The present proposal for renewal of #P01NS045260 funding, addresses this hypothesis. Program studies have shown that LTP stabilization is impaired in rodent models of six different types of memory disorder: middle-aging, early-stage Huntington's Disease (HD), Fragile-X Syndrome (FXS), Angelman Syndrome, short-term stress, and low estrogen levels. In each instance thus far tested, LTP-related reorganization of the spine cytoskeleton was defective and infusions and/or upregulating Brain-Derived Neurotrophic Factor (BDNF) rescued LTP and cytoskeletal changes. Moreover, activity-driven actin remodeling was shown to involve distinct cascades mediating spine F-actin assembly and stabilization, that are differentially impaired across the animal models, but both facilitated by BDNF. The proposed studies build on these findings to: i) identify defects in activity-driven signaling to actin, associated with LTP, in seven distinctly different rodent models of memory impairment;ii) determine if behaviorally induced actin signaling and learning is impaired in the rodent models;iii) test if chronic up-regulation of BDNF protein content increases signaling through BDNF's TrkB receptor and actin regulatory cascades as assessed in vitro and in vivo;and iv) test the prediction that the latter effects are accompanied by a reduction in behavioral abnormalities in each of the rodent models. There will be four Projects, directed by different PIs: each with its own rodent models and with different aspects of cytoskeletal signaling as a focus. Core A will provide analytical facilities for microscopy, electrophysiology, behavioral studies, and select neurochemical assays employed by all projects, and will support Administrative and Animal/Reagent functions. In all, the proposed studies are expected to test for the presence of a final, common defect in memory disorders and to thoroughly evaluate a clinically relevant strategy for normalizing synaptic plasticity and behavior.

Public Health Relevance

Currently no treatments exist for memory and cognitive impairments that afflict a significant portion of the adult population. Moreover, very little is known about the origins of these problems. The proposed studies will test if, in several conditions of different origin, cognitive impairments arise from a shared neurobiological problem. Studies will also test a novel, pharmacologically plausible strategy for treating these memory disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS045260-09
Application #
8253696
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Mamounas, Laura
Project Start
2002-12-01
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$1,233,419
Indirect Cost
$355,121
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Bi, Xiaoning; Sun, Jiandong; Ji, Angela X et al. (2016) Potential therapeutic approaches for Angelman syndrome. Expert Opin Ther Targets 20:601-13
Baudry, Michel; Bi, Xiaoning (2016) Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration. Trends Neurosci 39:235-45
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
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
Lauterborn, Julie C; Palmer, Linda C; Jia, Yousheng et al. (2016) Chronic Ampakine Treatments Stimulate Dendritic Growth and Promote Learning in Middle-Aged Rats. J Neurosci 36:1636-46
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 105:471-7
Wang, Weisheng; Kantorovich, Svetlana; Babayan, Alex H et al. (2016) Estrogen's Effects on Excitatory Synaptic Transmission Entail Integrin and TrkB Transactivation and Depend Upon β1-integrin function. Neuropsychopharmacology 41:2723-32
Liu, Yan; Sun, Jiandong; Wang, Yubin et al. (2016) Deleting both PHLPP1 and CANP1 rescues impairments in long-term potentiation and learning in both single knockout mice. Learn Mem 23:399-404

Showing the most recent 10 out of 94 publications