Autism is a devastating condition which takes a significant toll on patients, their families, and the national economy. There are no treatments for cognitive impairments (e.g., learning and memory deficits) that affect over 75% of autistic patients. In models of many autism-associated disorders and conditions with comorbidity for autism, such Fragile X, Rett, and Angelman Syndromes, there are significant abnormalities in dendritic spine morphology, which are associated with impairments in the stabilization of long-term potentiation (LTP), a synaptic mechanism of memory encoding. Together, these findings suggest that defects in the spine actin cytoskeleton may underlie cognitive deficits in autism-associated conditions of different origin. Spine abnormalities and LTP impairments are best characterized in the Fmr1-knockout (KO) mouse model of fragile X syndrome (FXS), a condition with high (~30%) comorbidity for autism. Specifically, these mutants exhibit defects in signaling through Rac GTPase, stabilization of activity-driven changes in spine filamentous (F) actin, and consolidation of LTP. Studies by the applicant have demonstrated that movement of cortactin, a spine protein which stabilizes actin network branch points and protects F-actin from degradation, via both actomyosin and microtubule systems, is impaired at Fmr1-KO spines following LTP-induction. This suggests that the F- actin stabilization deficits in KOs may reflect disturbances in signaling to cortactin. The proposed research will build on these findings to test the specific hypotheses that (a) abnormal cortactin serine phosphorylation and acetylation, which regulate the protein's subcellular movement, both originate from a single molecular impairment and contribute to the phenotype of impaired movement following LTP induction in KOs and that (b) learning (in vivo) activates these synaptic processes in WT but not KO mice. There are 3 specific aims.
Aim 1 will test if basal levels or activation of synaptic Ras or PP2A are impaired in KOs (both of these targets influence the cortactin phosphorylation and acetylation paths).
Aim 2 will test if signaling through MAPK and/or HDAC6, which contribute to cortactin serine phosphorylation and acetylation, are necessary for activity- induced cortactin translocation. hippocampus-dependent spatial learning activates synaptic signaling to cortactin in the WTs and if this signaling is attenuated or absent in Fmr1-KOs in vivo. Through interrogating synaptic mechanisms associated with impairments in F-actin stabilization and determining if these abnormalities are also present in the behaving animal, the proposed studies will contribute to our understanding of synaptic plasticity in both normal and FXS model mice and offer therapeutic targets for normalization of memory function in FXS and other autistic conditions. Finally, Aim 3 will test if hippocampus-dependent spatial learning activatessynaptic signaling to cortactin in the WTs and if this signaling is attenuated or absent in Fmr1-KOs in vivo. Through interrogating synaptic mechanisms associated with impairments in F-actin stabilization and determining if these abnormalities are also present in the behaving animal, the proposed studies will contribute to our understanding of synaptic plasticity in both normal and FXS model mice and offer therapeutic targets for normalization of memory function in FXS and other autistic conditions.

Public Health Relevance

There are no available therapeutics for the cognitive component (e.g. learning and memory impairments) of autism, a disease with increasing incidence and staggering national costs. Building upon novel findings that stabilization of the actin cytoskeleton is abnormal in a mouse model of a disease highly associated with autism, fragile X syndrome, the proposed research will test the hypotheses that modulation of the actin-associated protein cortactin is impaired in fragile X model mice and that these regulatory pathways are critically involved in the protein's cellular functions that are engaged during learning. This work is directly relevant to public health issues by advancing our understanding of cellular processes underlying cognitive impairment with autism, a highly prevalent condition with no known cure. Moreover, and importantly, these studies are expected to identify important therapeutic targets for improving cognitive (learning) function in fragile X syndrome and potentially other autism associated disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30MH095432-03
Application #
8658475
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Rosemond, Erica K
Project Start
2012-04-10
Project End
2016-07-09
Budget Start
2014-04-10
Budget End
2015-04-09
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Irvine
State
CA
Country
United States
Zip Code
92697
Muscianese, Laura; Seese, Ronald R; Graham, William et al. (2015) Congenital atresia of the inferior vena cava and antithrombin III deficiency in a young adult: compounding risk factors for deep vein thrombosis. BMJ Case Rep 2015:
Seese, Ronald R; Wang, Kathleen; Yao, Yue Qin et al. (2014) Spaced training rescues memory and ERK1/2 signaling in fragile X syndrome model mice. Proc Natl Acad Sci U S A 111:16907-12
Ozkan, Emin D; Creson, Thomas K; Kramár, Enikö A et al. (2014) Reduced cognition in Syngap1 mutants is caused by isolated damage within developing forebrain excitatory neurons. Neuron 82:1317-33
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
Andres, Adrienne L; Regev, Limor; Phi, Lucas et al. (2013) NMDA receptor activation and calpain contribute to disruption of dendritic spines by the stress neuropeptide CRH. J Neurosci 33:16945-60
Seese, Ronald R; Chen, Lulu Y; Cox, Conor D et al. (2013) Synaptic abnormalities in the infralimbic cortex of a model of congenital depression. J Neurosci 33:13441-8
Seese, Ronald R; Babayan, Alex H; Katz, Adam M et al. (2012) LTP induction translocates cortactin at distant synapses in wild-type but not Fmr1 knock-out mice. J Neurosci 32:7403-13
Jafari, Matiar; Seese, Ronald R; Babayan, Alex H et al. (2012) Glucocorticoid receptors are localized to dendritic spines and influence local actin signaling. Mol Neurobiol 46:304-15