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dc.contributor.advisorKensuke Futai
dc.contributor.authorMao, Wenjie
dc.date2022-08-11T08:08:46.000
dc.date.accessioned2022-08-23T16:07:51Z
dc.date.available2022-08-23T16:07:51Z
dc.date.issued2017-12-07
dc.date.submitted2018-01-18
dc.identifier.doi10.13028/M2B69Q
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32331
dc.description<p>Data are available for download under "Additional Files."</p>
dc.description.abstractInformation 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.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectsynaptic plasticity
dc.subjecthomeostatic plasticity
dc.subjecthomeostatic scaling
dc.subjectsynaptic scaling
dc.subjectexcitatory and inhibitory balance
dc.subjecthippocampus
dc.subjectepigenetics
dc.subjectchromatin reader
dc.subjectMBT
dc.subjectinterneuron
dc.subjectparvalbumin
dc.subjectshank
dc.subjectsynaptic scaffolding molecule
dc.subjectautism spectrum disorders
dc.subjectmouse model
dc.subjectMolecular and Cellular Neuroscience
dc.titleMolecular Players in Preserving Excitatory-Inhibitory Balance in the Brain
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1953&amp;context=gsbs_diss&amp;unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/947
dc.legacy.embargo2019-01-18T00:00:00-08:00
dc.identifier.contextkey11382110
dc.file.descriptionTable 2.2 Datasets for RNA-seq
dc.file.descriptionTable 2.3 Datasets for ChIP-seq
refterms.dateFOA2022-08-24T04:10:54Z
html.description.abstract<p>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.</p>
dc.identifier.submissionpathgsbs_diss/947
dc.contributor.departmentFutai Lab
dc.contributor.departmentNeurobiology
dc.description.thesisprogramNeuroscience
dc.identifier.orcid0000-0002-6434-2216


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