AUTHOR=Mingote Susana , Masson Justine , Gellman Celia , Thomsen Gretchen M. , Lin Chyuan-Sheng , Merker Robert J. , Gaisler-Salomon Inna , Wang Yvonne , Ernst Rachel , Hen René , Rayport Stephen TITLE=Genetic Pharmacotherapy as an Early CNS Drug Development Strategy: Testing Glutaminase Inhibition for Schizophrenia Treatment in Adult Mice JOURNAL=Frontiers in Systems Neuroscience VOLUME=Volume 9 - 2015 YEAR=2016 URL=https://www.frontiersin.org/journals/systems-neuroscience/articles/10.3389/fnsys.2015.00165 DOI=10.3389/fnsys.2015.00165 ISSN=1662-5137 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 CAGERT2