Advisory Committee Chair
Erik D Roberson
Advisory Committee Members
Lori L McMahon
David G Standaert
Rosalinda C Roberts
Robin G Lorenz
Document Type
Dissertation
Date of Award
2014
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Frontotemporal dementia (FTD) is a rapidly progressive and lethal disease, with no disease-modifying treatments. It is known that tau mutations cause FTD, but the underlying neurobiology is undefined. We sought to identify how tau affects the neurobiology in order to find potential treatment targets. Here, we address this question using a new mouse model expressing human tau with an FTD-associated mutation. We studied behavior, physiology, biochemistry, and neuropathology in several cohorts of mice at different ages. These mutant tau mice had abnormal repetitive behavior characteristic of FTD and synaptic deficits selectively in regions associated with FTD (ventral striatum and insula). There, mutant tau depleted PSD-95 and impaired synaptic localization of glutamate receptors, including NMDA receptors (NMDAR). Recordings from ventral striatum neurons revealed deficits in NMDAR-mediated synaptic transmission, resulting in impaired network activity. Pharmacologically targeting NMDAR hypofunction in vivo with cycloserine, an FDA-approved NMDAR co-agonist, reversed network impairments and repetitive behavior. These results indicate that mutant tau impairs NMDAR trafficking, causing NMDAR hypofunction in vulnerable brain regions, and that this process can be therapeutically targeted. These findings have important treatment implications, including the possibility of repurposing cycloserine for treating FTD.
Recommended Citation
Warmus, Brian Andrew, "Targeting Tau-Mediated Nmdar Hypofunction Reverses Deficits In A Mouse Model Of Frontotemporal Dementia" (2014). All ETDs from UAB. 3267.
https://digitalcommons.library.uab.edu/etd-collection/3267
