Advisory Committee Chair
J David Sweatt
Advisory Committee Members
Candace L Floyd
Fang-Tsyr Lin
Gavin R Rumbaugh
Harald W Sontheimer
Scott M Wilson
Document Type
Dissertation
Date of Award
2011
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Protease-activated receptor-1 (PAR1) is an unusual G-protein coupled receptor (GPCR) that is activated through proteolytic cleavage by extracellular serine proteases. While previous work has shown that inhibiting PAR1 activation is neuroprotective in models of ischemia, traumatic injury, and neurotoxicity, surprisingly little is known about PAR1's contribution to normal brain function. In the central nervous system (CNS), PAR1 is expressed in glial cells in the hippocampus, a brain region critical for memory formation. I am particularly interested in PAR1 because its activation enhances the function of N-methyl-D-aspartate receptors (NMDARs), which are required for some forms of behavioral learning and synaptic plasticity. Thus, the work in this dissertation is driven by the central hypothesis that PAR1 function is a regulator of NMDAR-dependent memory formation and synaptic function. In this dissertation, I explore the consequences of loss of PAR1 function on long-term memory formation and long-term synaptic plasticity in the PAR1 -/- mouse. I demonstrate that whereas baseline behavioral measures were largely unaffected by PAR1 removal, PAR1-/- mice showed deficits in hippocampus-dependent memory tasks. I also show that while PAR1 -/- mice have normal baseline synaptic transmission at Schaffer collateral-CA1synapses, they exhibit severe deficits in NMDAR-dependent long-term potentiation (LTP). Mounting evidence indicates that PAR1 is expressed predominantly in astrocytes in the hippocampus, and that activation of PAR1 leads to glutamate release from astrocytes and potentiation of NMDAR responses in CA1 pyramidal cells. Taken together, these data suggest an important role for PAR1 function in astrocyte-neuron interactions subserving memory formation and synaptic plasticity.
Recommended Citation
Almonte, Antoine Gabriel, "The Role of Protease-Activated Receptor-1 in Synaptic Plasticity and Memory" (2011). All ETDs from UAB. 1005.
https://digitalcommons.library.uab.edu/etd-collection/1005