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Abstract: We have shown that Wnt signaling is activated in the hippocampus 5
days following status epilepticus (SE), and that Wnt signaling activates a Warburg-like
metabolic program. We hypothesized that Wnt-signaling induced Warburg metabolism
contributes to the ratio of GABA to glutamate, which is a critical factor in the
progression to chronic seizures and whose syntheses derive from TCA c... read moreycle intermediates. To
probe the role of Wnt signaling, we used HBP1 knockout mice (HBP1-/-). HBP1 is a Wnt
signaling inhibitor; is expressed in hippocampal CA1-CA3; and may have human genetic
association with seizures. Specifically, HBP1-/- mice should have elevated Wnt signaling,
and provide a means of analyzing the proposed model. Our biochemical analysis shows that
HBP1-/- mice have high Wnt signaling; decreased AMPK phosphorylation; and high mTOR
signaling in hippocampal extracts. HBP1-/- mice have spontaneous seizures and have elevated
sensitivity to pilocarpine induction of SE. Furthermore, glutamine synthase and glutaminase
expression were significantly changed, as well as the expression of glutamate transporter;
EAAT3 neuronal transporter and GLT-1 astrocytic transporter. Coupled with these changes
were a marked increase in gliosis, suggesting that astrocyte expansion and metabolism may
play a role in the pathogenesis of seizures in HBP1 knockout model.
Thesis (M.S.)--Tufts University, 2018.
Submitted to the Dept. of Pharmacology and Drug Development.
Advisor: Amy Yee.
Committee: Eric Paulson.
Keyword: Pharmacology.read less
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