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    Molecular Players in Preserving Excitatory-Inhibitory Balance in the Brain

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    Authors
    Mao, Wenjie
    Faculty Advisor
    Kensuke Futai
    Academic Program
    Neuroscience
    UMass Chan Affiliations
    Futai Lab
    Neurobiology
    Document Type
    Doctoral Dissertation
    Publication Date
    2017-12-07
    Keywords
    synaptic plasticity
    homeostatic plasticity
    homeostatic scaling
    synaptic scaling
    excitatory and inhibitory balance
    hippocampus
    epigenetics
    chromatin reader
    MBT
    interneuron
    parvalbumin
    shank
    synaptic scaffolding molecule
    autism spectrum disorders
    mouse model
    Molecular and Cellular Neuroscience
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    Abstract
    Information processing in the brain relies on a functional balance between excitation and inhibition, the disruption of which leads to network destabilization and many neurodevelopmental disorders, such as autism spectrum disorders. One of the homeostatic mechanisms that maintains the excitatory and inhibitory balance is called synaptic scaling: Neurons dynamically modulate postsynaptic receptor abundance through activity-dependent gene transcription and protein synthesis. In the first part of my thesis work, I discuss our findings that a chromatin reader protein L3mbtl1 is involved in synaptic scaling. We observed that knockout and knockdown of L3mbtl1 cause a lack of synaptic downscaling of glutamate receptors in hippocampal primary neurons and organotypic slice cultures. Genome-wide mapping of L3mbtl1 protein occupancies on chromatin identified Ctnnb1 and Gabra2 as downstream target genes of L3mbtl1-mediated transcriptional regulation. Importantly, partial knockdown of Ctnnb1 by itself prevents synaptic downscaling. Another aspect of maintaining E/I balance centers on GABAergic inhibitory neurons. In the next part of my thesis work, we address the role of the scaffold protein Shank1 in excitatory synapses onto inhibitory interneurons. We showed that parvalbumin-expressing interneurons lacking Shank1 display reduced excitatory synaptic inputs and decreased levels of inhibitory outputs to pyramidal neurons. As a consequence, pyramidal neurons in Shank1 mutant mice exhibit increased E/I ratio. This is accompanied by a reduced expression of an inhibitory synapse scaffolding protein gephyrin. These results provide novel insights into the roles of chromatin reader molecules and synaptic scaffold molecules in synaptic functions and neuronal homeostasis.
    DOI
    10.13028/M2B69Q
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32331
    Notes

    Data are available for download under "Additional Files."

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    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2B69Q
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses
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