All ETDs from UAB

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.

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