Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice

Frontiers in Systems Neuroscience
Susana MingoteStephen Rayport

Abstract

Genetic pharmacotherapy is an early drug development strategy for the identification of novel CNS targets in mouse models prior to the development of specific ligands. Here for the first time, we have implemented this strategy to address the potential therapeutic value of a glutamate-based pharmacotherapy for schizophrenia involving inhibition of the glutamate recycling enzyme phosphate-activated glutaminase. Mice constitutively heterozygous for GLS1, the gene encoding glutaminase, manifest a schizophrenia resilience phenotype, a key dimension of which is an attenuated locomotor response to propsychotic amphetamine challenge. If resilience is due to glutaminase deficiency in adulthood, then glutaminase inhibitors should have therapeutic potential. However, this has been difficult to test given the dearth of neuroactive glutaminase inhibitors. So, we used genetic pharmacotherapy to ask whether adult induction of GLS1 heterozygosity would attenuate amphetamine responsiveness. We generated conditional floxGLS1 mice and crossed them with global CAG(ERT2cre∕+) mice to produce GLS1 iHET mice, susceptible to tamoxifen induction of GLS1 heterozygosity. One month after tamoxifen treatment of adult GLS1 iHET mice, we found a 50% reductio...Continue Reading

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Citations

Dec 25, 2016·Neurochemical Research·Javier MárquezFernando Rodríguez de Fonseca
Jul 14, 2017·ELife·Susana MingoteStephen Rayport
Dec 16, 2018·Cellular and Molecular Neurobiology·Lauren KostenSteven Staelens
Dec 6, 2020·The Journal of Biological Chemistry·Silvia NitschkeBerge A Minassian
Oct 30, 2020·Nature·Min ShangMassimiliano Mazzone
Jun 8, 2021·Frontiers in Neural Circuits·Daniel EskenaziNao Chuhma

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Methods Mentioned

BETA
pharmacotherapy
pharmacotherapies
PCR
genotyping
restriction digest
electrophoresis

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