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Neurotransmitter and their metabolite concentrations in different areas of the HPRT knockout mouse brain

Published:April 16, 2016DOI:https://doi.org/10.1016/j.jns.2016.04.025

      Highlights

      • Neurotransmitter concentrations vary in different mouse brain areas.
      • Investigated neurotransmitter systems in HPRT knockout mice are unaltered.
      • Mice may be able to partly compensate for HPRT deficiency in the brain.

      Abstract

      Lesch–Nyhan syndrome (LNS) is characterized by uric acid overproduction and severe neurobehavioral symptoms, such as recurrent self-mutilative behavior. To learn more about the pathophysiology of the disease, we quantified neurotransmitters and their metabolites in the cerebral hemisphere, cerebellum and the medulla oblongata of HPRT knockout mice, an animal model for LNS, in comparison to the corresponding wild-type. Our analyses included l-glutamate, 4-aminobutanoic acid (GABA), acetylcholine, serotonin, 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine, l-normetanephrine, epinephrine and l-metanephrine and were conducted via high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS). Among these neurotransmitter systems, we did not find any abnormalities in the HPRT knockout mouse brains. On one side, this might indicate that HPRT deficiency most severely affects dopamine signaling, while brain functioning based on other neurotransmitters is more or less spared. On the other hand, our findings may reflect a compensating mechanism for impaired purine salvage that protects the brain in HPRT-deficient mice but not in LNS patients.

      Abbreviations:

      5-HIAA (5-hydroxyindoleacetic acid), d4-dopamine (2-(3,4-dihydroxyphenyl)ethyl-1,1,2,2-d4-amine HCl), d4-histamine (histamine-d4 diHCl), d5-DOPAC (3,4-dihydroxyphenylacetic acid (ring-d3, 2,2-d2)), d6-norepinephrine ((±)-norepinephrine-2,5,6,α,β,β-d6 HCl), DHPG (3,4-dihydroxyphenylethyleneglycol), GABA (4-aminobutanoic acid), HILIC (hydrophilic interaction liquid chromatography), HPLC (high performance liquid chromatography), HPRT (hypoxanthine-guanine phosphoribosyltransferase), HPRT− (HPRT knockout mice), LLOQ (lower limit of quantification), LNS (Lesch–Nyhan syndrome), MS/MS (tandem mass spectrometry), QC (quality control), SD (standard deviation), WT (wild-type mice)

      Keywords

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