WWC2 Is a Novel Regulator of GABAAR Expression, Synaptic Function, and Dendritic Morphology in Excitatory Hippocampal Neurons

The members of the WWC protein family have been implicated in numerous neurodevelopmental, neuropsychiatric, and neurodegenerative disorders, including autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, Alzheimer disease, and Huntington's disease. Despite the wide range of pathologies associated with WWC proteins, only WWC1 (KIBRA) has been the subject of functional or mechanistic study in the central nervous system. Here, I present the first data describing the function of WWC2 in the mammalian hippocampus. Using a forebrain-specific knockout model, I demonstrate that WWC2 negatively regulates surface GABAAR expression in the 1-month-old mouse hippocampus. Additionally, I demonstrate that the GABAAR recycling regulators HAP1 and GRIP1 are overexpressed in the membrane fraction of WWC2 KO hippocampal tissue, suggesting that WWC2 regulates GABAAR recycling. These changes to receptor expression and trafficking are specific for GABAARs, as WWC2 KO animals have unchanged expression of AMPAR subunits GluA1 and GluA2. I further make use of conditional knockout models to show that WWC2 loss leads to dysregulated baseline synaptic function and decreased dendritic branching in hippocampal neurons. Preliminary studies indicate that CA1 pyramidal cells from WWC2 KO animals exhibit a trend toward increased stubby spine representation on basal dendrites. Additionally, I report preliminary data describing deficits in GABAAR expression and trafficking in the adult WWC2 KO and heterozygous KO hippocampus, indicating that regulation of GABAAR expression and trafficking by WWC2 is likely age-dependent. Finally, I describe hypothetical mechanisms by which WWC2 may regulate GABAAR recycling and basal synaptic strength. In Chapter 1, I review the relevant literature which has shaped this dissertation. In Chapter 2, I present data which show that loss of WWC2 leads to overexpression of surface GABAARs, dysregulated synaptic strength, and decreased dendritic branching in hippocampal neurons. In Chapter 3, I describe preliminary data on the effects of WWC2 loss on dendritic spine morphology and adult GABAAR expression, as well as evidence that WWC2 may interact with GABAARs and KIBRA. In Chapter 4, I describe the implications of this work and propose additional lines of experimentation to further clarify the function of WWC2 in the brain.

Author dc:creator

• Dunham, Thomas Leigh

Contributors dc:contributor

• Huber, Kimberly M.
• Konopka, Genevieve
• Pan, Duojia
• Volk, Lenora J.

• Receptors, GABA-A
• Synapses
• Adaptor Proteins, Signal Transducing
• Synaptic Transmission

Language dc:language

en

Identifier

1522122344

OAI identifier oai:identifier

oai:utswmed-ir.tdl.org:2152.5/10582