The small size of dendritic spines belies the elaborate role they play in excitatory synaptic transmission and ultimately complex behaviors. The cytoskeletal architecture of the spine is predominately composed of actin filaments. These filaments, which at first glance might appear simple, are also surprisingly complex. They dynamically assemble into different structures and serve as a platform for orchestrating the elaborate responses of the spine during spinogenesis and experience-dependent plasticity. Mutations in pathways that regulate synaptic actin in humans and mice are associated with neurological disorders (humans) and related endophenotypes (mice). My laboratory studies a signaling pathway that drives de novo actin polymerization in spines by the activation of WAVE1 downstream of Rac. The objective of this application is to analyze epistasis between Fmr1, the causative gene in Fragile X Syndrome, and WAVE1. Our central hypothesis is that elevated WAVE1 and dysregulation of actin significantly contributes to the synaptic and behavioral phenotypes of Fragile X Syndrome. This hypothesis is guided by strong preliminary data based on: 1) In Fmr1 null mice, Rac activity is elevated and inhibition of Rac normalizes LTD. 2) Our previous work showing that loss of WAVE1 results in synaptic phenotypes opposite those of Fmr1 loss. 3) WAVE1 mRNA is a direct target of FMRP and our preliminary data shows an increase in WAVE1 protein in Fmr1 null mice. 4) Our data that demonstrates that mGluR activation reorganizes spine actin and that synaptic actin dynamics are significantly altered in a mouse model of FXS. 5) Our preliminary data showing Fmr1 null memory impairments are rescued in mice also heterozygous for Wave1.
The specific aims of this grant are: 1) Quantitatively analyze the link between spine actin dynamics and loss of FMRP. 2) Test if genetic reduction of WAVE1 normalizes Fmr1 null deficits. 3) Test for mimicry of Fmr1 null phenotypes by WAVE1 overexpression in vivo. Because this proposal utilizes a multidisciplinary approach to analyze how loss of Fmr1 results in abnormal WAVE1 levels, altered spine actin dynamics, synaptic plasticity, and behavioral deficits, a fundamental advance in understanding the mechanisms linking actin signaling to neuronal dysfunction in a model of Fragile X Syndrome can be anticipated. Thus the proposed research is relevant to that part of NIH's mission that pertains to the investigation of the mechanisms linking genetic mutations to mechanisms of neurological disease.
This research is relevant to the mission of NIH because it examines the functional role of a signaling pathway implicated in intellectual disability disorders at the behavioral and synaptic level. The focus of this application is on Fragile X Syndrome and how the synaptic and behavioral phenotypes may be modified by postsynaptic actin signaling via WAVE1. Thus, important advances in understanding the etiology of Fragile X Syndrome could be anticipated. It is also expected that knowledge gained in these studies will shed light on other forms of neurodevelopmental disorders that involve abnormal signaling to the actin cytoskeleton in excitatory dendritic spines and mechanisms that normally regulate neuronal connectivity.
|Yan, Zhen; Kim, Eunjoon; Datta, Dibyadeep et al. (2016) Synaptic Actin Dysregulation, a Convergent Mechanism of Mental Disorders? J Neurosci 36:11411-11417|
|Spence, Erin F; Kanak, Daniel J; Carlson, Benjamin R et al. (2016) The Arp2/3 Complex Is Essential for Distinct Stages of Spine Synapse Maturation, Including Synapse Unsilencing. J Neurosci 36:9696-709|
|Kim, Il Hwan; Rossi, Mark A; Aryal, Dipendra K et al. (2015) Spine pruning drives antipsychotic-sensitive locomotion via circuit control of striatal dopamine. Nat Neurosci 18:883-91|
|Spence, Erin F; Soderling, Scott H (2015) Actin Out: Regulation of the Synaptic Cytoskeleton. J Biol Chem 290:28613-22|
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|Kim, Il Hwan; Wang, Hong; Soderling, Scott H et al. (2014) Loss of Cdc42 leads to defects in synaptic plasticity and remote memory recall. Elife 3:|
|Zhou, Kang; Muroyama, Andrew; Underwood, Julie et al. (2013) Actin-related protein2/3 complex regulates tight junctions and terminal differentiation to promote epidermal barrier formation. Proc Natl Acad Sci U S A 110:E3820-9|
|Burianek, Lauren E; Soderling, Scott H (2013) Under lock and key: spatiotemporal regulation of WASP family proteins coordinates separate dynamic cellular processes. Semin Cell Dev Biol 24:258-66|
|Kim, Il Hwan; Racz, Bence; Wang, Hong et al. (2013) Disruption of Arp2/3 results in asymmetric structural plasticity of dendritic spines and progressive synaptic and behavioral abnormalities. J Neurosci 33:6081-92|
|Okada, Hirokazu; Uezu, Akiyoshi; Soderblom, Erik J et al. (2012) Peptide array X-linking (PAX): a new peptide-protein identification approach. PLoS One 7:e37035|
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