Biochim Biophys Acta Mol Basis Dis. 2019 Jan;1865(1):193-205. doi: 10.1016/j.bbadis.2018.08.018. Epub 2018 Aug 16.
Jeanclos, E; Albersen, M; Ramos, RJJ; Raab, A; Wilhelm, C; Hommers, L; Lesch, KP; Verhoeven-Duif, NM; Gohla, A
Institute of Pharmacology and Toxicology, University of Würzburg, Germany; Interdisciplinary Center for Clinical Research, University Hospital Würzburg, Germany; Comprehensive Heart Failure Center, University Hospital Würzburg, Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, Germany. Department of Genetics, University Medical Center Utrecht, the Netherlands. Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia. Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
Pyridoxal 5'-phosphate (PLP) is an essential cofactor in the catalysis of ~140 different enzymatic reactions. A pharmacological elevation of cellular PLP concentrations is of interest in neuropsychiatric diseases, but whole-body consequences of higher intracellular PLP levels are unknown. To address this question, we have generated mice allowing a conditional ablation of the PLP phosphatase PDXP. Ubiquitous PDXP deletion increased PLP levels in brain, skeletal muscle and red blood cells up to 3-fold compared to control mice, demonstrating that PDXP acts as a major regulator of cellular PLP concentrations in vivo. Neurotransmitter analysis revealed that the concentrations of dopamine, serotonin, epinephrine and glutamate were unchanged in the brains of PDXP knockout mice. However, the levels of γ-aminobutyric acid (GABA) increased by ~20%, demonstrating that elevated PLP levels can drive additional GABA production. Behavioral phenotyping of PDXP knockout mice revealed improved spatial learning and memory, and a mild anxiety-like behavior. Consistent with elevated GABA levels in the brain, PDXP loss in neural cells decreased performance in motor tests, whereas PDXP-deficiency in skeletal muscle increased grip strength. Our findings suggest that PDXP is involved in the fine-tuning of GABA biosynthesis. Pharmacological inhibition of PDXP might correct the excitatory/inhibitory imbalance in some neuropsychiatric diseases.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 350 scientific publications are based on research using Ozgene mice.