This proposal is designed to determine the synaptic and molecular mechanisms underlying repetitive behavior in ventral striatum of a mouse model of frontotemporal dementia (FTD). Tau mutations cause FTD, and we have found several FTD-relevant behavioral abnormalities in a transgenic mouse expressing the V337M human tau mutation (hTauV337M mice). We found that these mice have repetitive behavior, a core feature of FTD. hTauV337M mice have decreased excitatory transmission and altered synaptic organization in ventral striatum, which is an important mediator of repetitive behaviors in FTD. Preliminary data suggests that hTauV337M mice may have impaired NMDA receptor signaling and decreased surface AMPA receptor trafficking. We hypothesize that mutant tau protein causes repetitive behavior due to synaptic dysfunction in ventral striatum, which results from impaired NMDAR signaling causing reduced surface AMPA receptor trafficking To determine if surface AMPAR trafficking is decreased in ventral striatum of hTauV337M mice, we will measure surface AMPAR levels at the synapse by biotinylation and biochemical fractionation of ventral striatum. In addition, we will determine the functionality of surface AMPARs by recording mEPSC amplitude and frequency from acute striatal slices. To determine if NMDAR signaling is impaired in hTauV337M mice we will pharmacologically isolate and compare NMDA receptor-mediated EPSCs from acute striatal slices. We will determine if increasing NMDAR signaling with a co-agonist, D-cycloserine, can increase surface AMPAR trafficking at the synapse by measuring the synaptic surface expression of AMPARs after treatment. We will determine if increasing NMDAR signaling with a D-cycloserine can correct the decreased excitatory transmission by recording from acute striatal slices after treatment. Lastly, we will determine if increasing NMDAR signaling with a co-agonist can correct repetitive behaviors by comparing untreated and treated mice. The proposed research training plan is sponsored by Dr. Erik Roberson and co-sponsored by Dr. Lori McMahon. The overall goal of the training plan is to provide the PI an enhanced repertoire of laboratory techniques, a solid foundation in hypothesis-driven approaches in neurobiology research, and other skills necessary for a successful career as a physician scientist. Currently, there have yet to be any disease-modifying treatments for FTD and other fatal neurodegenerative diseases. The results from this proposal will help identify potential treatment targets and help direct future studies on the causes, prevention, and treatment of FTD.
Frontotemporal dementia is a common dementia at a relatively young age (45-65 years old) that drastically changes one's personality and behaviors, often when people are at the pinnacle of their careers and highly contributive to society. Unfortunately, there have yet to be any disease-modifying treatments for this rapidly progressive and fatal disease. We aim to address this by studying the synaptic and molecular mechanisms underlying behavioral abnormalities in a mouse model of FTD, to find potential treatment targets that can help direct therapeutic development.
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