GSBS Dissertations and Theses

ORCID ID

0000-0002-6434-2216

Approval Date

12-7-2017

Document Type

Doctoral Dissertation

Academic Program

Neuroscience

Department

Neurobiology; Futai Lab

First Thesis Advisor

Kensuke Futai

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

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

Rights and Permissions

Copyright is held by the author, with all rights reserved.

Available for download on Friday, January 18, 2019

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