• Login as Editor
    View Item 
    •   Yeshiva Academic Institutional Repository
    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
    • View Item
    •   Yeshiva Academic Institutional Repository
    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Metabotropic regulation of dendritic spine structural plasticity

    Thumbnail

    Date
    2015
    Author
    Kalinowska, Magdalena
    Metadata
    Show full item record
    Share
    Abstract
    Synaptic plasticity is often accompanied by morphological alterations of dendritic spines, small protrusions formed on neuronal dendritic shafts and sites of most excitatory synapses. Changes in dendritic spine morphogenesis are hypothesized to be the physical correlate of memory. Relationship between synaptic structure and function is further underscored by observations that spine dysgenesis accompanies many neurodevelopmental disorders including Fragile X syndrome, autism and schizophrenia, although how abnormal spine morphology contributes to cognitive and behavioral impairments is not known. Understanding how neuronal activity mobilizes molecular effectors that drive structural modifications in dendritic spines will enhance our understanding of basic memory processes and help to identify pharmacological targets for treatment of neurodevelopmental disorders. My thesis research explored molecular mechanisms underlying dendritic spines morphogenesis and their regulation by glutamatergic neurotrasmission via group 1 metabotropic glutamate receptors (Gp1 mGluRs). Gp1 mGluRs are G protein coupled receptors critical to development of brain circuitry, activity-dependent synaptic plasticity and are implicated in neuropsychiatric disorders such as Fragile X syndrome, autism and schizophrenia. Moreover, Gp1 mGluRs participate in dendritic spine remodeling and administration of mGluR antagonists can correct spine abnormalities in Fmr1 knockout mice, an animal model of Fragile X syndrome. Molecular effectors linking receptor activity to plastic changes in spines remain uncharacterized. My research identified the actin-binding protein aactinin-4 (actinin-4) as a novel Gp1 mGluR binding partner that orchestrates spine dynamics and morphogenesis in neurons and plays an essential role in regulation of dendritic spine morphogenesis downstream of Gp1 mGluRs. Actinin-4 overexpression was sufficient to modify spine morphogenesis, the latter function dependent on actinin-4 C-terminal domain that mediates CaMKII binding and I showed that this interaction is regulated by Gp1 mGluRs. Furthermore, I discovered that actinin-4 interacts in the brain with synaptopodin, an actin-binding protein associated with the spine apparatus at a subset of mature, mushroom type dendritic spines that I hypothesized to be the locus of Gpl mGluR-dependent plasticity. I found that Gpl mGluRs and their signaling complex are selectively enriched at synaptic sites containing synaptopodin in mature neurons. Thus, my research enhanced our understanding of how this important class of glutamate receptors can regulate structural plasticity.
    Permanent Link(s)
    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:10014270
    https://hdl.handle.net/20.500.12202/359
    Citation
    Source: Dissertation Abstracts International, Volume: 77-07(E), Section: B.;Advisors: Anna Francesconi.
    *This is constructed from limited available data and may be imprecise.
    Collections
    • Albert Einstein College of Medicine: Doctoral Dissertations [1674]

    Yeshiva University Libraries copyright © 2021  DuraSpace
    YAIR Self-Deposit | YAIR User's Guide | Take Down Policy | Contact Us
    Yeshiva University
     

     

    Browse

    AllCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    Login as Editor

    Statistics

    View Usage Statistics

    Yeshiva University Libraries copyright © 2021  DuraSpace
    YAIR Self-Deposit | YAIR User's Guide | Take Down Policy | Contact Us
    Yeshiva University