Improved cognition, mild anxiety-like behavior and decreased motor performance in pyridoxal phosphatase-deficient mice

Elisabeth Jeanclos*, Monique Albersen, Ruben J. J. Ramos, Annette Raab, Christian Wilhelm, Leif Hommers, Klaus-Peter Lesch, Nanda M. Verhoeven-Duif, Antje Gohla*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Web of Science)

Abstract

Pyridoxal 5'-phosphate (PLP) is an essential cofactor in the catalysis of similar to 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 y-aminobutyric acid (GABA) increased by similar to 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.

Original languageEnglish
Pages (from-to)193-205
Number of pages13
JournalBiochimica et Biophysica Acta-Molecular Basis of Disease
Volume1865
Issue number1
DOIs
Publication statusPublished - Jan 2019

Keywords

  • Pyridoxal phosphatase
  • Vitamin B6
  • gamma-Aminobutyric acid (GABA)
  • Motor performance
  • Neuropsychiatric diseases
  • Neurotransmitter biosynthesis
  • NONSPECIFIC ALKALINE-PHOSPHATASE
  • GABA
  • CHRONOPHIN
  • 5'-PHOSPHATE
  • VITAMIN-B6
  • MECHANISM
  • METABOLISM
  • DEPRESSION
  • DISORDERS
  • MUTATIONS

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