The Integrated Role of Wnt Signaling, mTOR Signaling and Glutamate Metabolism as a Possible Drug Target for Epilepsy in HBP1-/- Mice
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 ... read morecycle 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
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