Efforts to identify causes of memory and cognition deficits in Fragile X Syndrome (FXS) led to the discovery of synaptic plasticity impairments in cortex of a knock-out mouse model (Fmr1-KO) of the disorder. The applicants have extended these results by showing that hippocampal long-term potentiation (LTP), induced by learning-related patterns of afferent activity, fails to stabilize in Fmr1-KO mice. Analysis of cytoskeletal changes required for lasting LTP pointed to the hypothesis that a critical FXS-defect involves failed stabilization of new actin filaments during the first few minutes after LTP induction. Preliminary results showing abnormal expression of several actin-associated proteins in the knockouts (KOs) support this argument. Objectives of the proposed studies are to (1) identify causes for the failure in filamentous (F) actin stabilization and LTP in Fmr1-KO mice, and (2) develop treatments for normalizing cytoskeletal changes and stable LTP. Pilot studies have shown that treatment with the mGluR5 antagonist MPEP, or with a positive AMPA receptor modulator (ampakine), can restore stable LTP to Fmr1-KO hippocampus. Further results indicate that both drugs also reverse measures of aberrant spine morphology in the KOs. The proposed research will build on these findings in 4 specific aims.
Aim 1 will test the hypothesis that MPEP can normalize stabilization of spine F-actin and LTP in hippocampal slices from adult Fmr1-KO mice. Further studies will test if LTP impairments are offset by translation inhibitors and linked to aberrant signaling by integrin-associated tyrosine kinases.
Aim 2 will test if abnormal basal levels of actin regulatory proteins in Fmr1-KO dendritic spines lead to aberrations in TBS- induced signaling to the actin cytoskeleton. Studies will employ deconvolution immunofluorescent techniques to test effects of theta burst afferent stimulation on levels of target proteins in spines of KO and WT mice.
Aim 3 will use acute slices to test if MPEP and ampakine treatments have additive or synergistic effects in the rescue of hippocampal LTP in Fmr1-KO mice (3A). Follow on acute slice experiments will test if the treatments that rescue LTP also normalize (3B) pyramidal cell spine measures and (3C) levels and activity-induced changes in spine actin-regulatory proteins in hippocampal field CA1. Studies in Aim 4 complement those in Aim 3 to test if drugs that rescue hippocampal LTP also restore stable potentiation (4A) and spine measures (4B) in slices from somatosensory neocortex of Fmr1-KO mice.
Aim 4 C will then test if in vivo treatments with an ampakine, MPEP, or both, normalize spine measures in somatosensory cortex and hippocampal field CA1.
Aims 3 and 4 will use Fmr1-KO and WT mice that constitutively express yellow fluorescent protein (YFP) in scattered pyramidal cells to provide a bright label of dendritic spines. These studies are expected to produce a specific explanation for why spine plasticity and structure are disturbed by the Fragile X mutation, and to generate potential therapies for correcting the defects.

Public Health Relevance

Efforts to identify causes of mental retardation associated with Fragile X Syndrome led to the discovery of synaptic plasticity impairments in a mouse model of the disorder. The present studies will test the hypothesis that impairments are due to abnormal levels of actin regulatory proteins, which are critical for changes in synaptic function during learning. Studies will also test potential therapeutics for correcting these synaptic defects that might improve learning in this syndrome and other autism spectrum disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH082042-04
Application #
8212113
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Asanuma, Chiiko
Project Start
2009-04-01
Project End
2013-10-31
Budget Start
2012-02-01
Budget End
2013-10-31
Support Year
4
Fiscal Year
2012
Total Cost
$369,178
Indirect Cost
$121,678
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
Seese, Ronald R; Maske, Anna R; Lynch, Gary et al. (2014) Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism. Neuropsychopharmacology 39:1664-73
Kramar, E A; Babayan, A H; Gall, C M et al. (2013) Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton. Neuroscience 239:3-16
Lynch, Gary; Kramar, Eniko A; Babayan, Alex H et al. (2013) Differences between synaptic plasticity thresholds result in new timing rules for maximizing long-term potentiation. Neuropharmacology 64:27-36
Hagerman, Randi; Lauterborn, Julie; Au, Jacky et al. (2012) Fragile X syndrome and targeted treatment trials. Results Probl Cell Differ 54:297-335
Simmons, Danielle A; Mehta, Rishi A; Lauterborn, Julie C et al. (2011) Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice. Neurobiol Dis 41:436-44
Chen, Lulu Y; Rex, Christopher S; Babayan, Alex H et al. (2010) Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome. J Neurosci 30:10977-84
Chen, Lulu Y; Rex, Christopher S; Pham, Danielle T et al. (2010) BDNF signaling during learning is regionally differentiated within hippocampus. J Neurosci 30:15097-101