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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of the Neurological SciencesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Genotype-phenotype correlations in neurogenetics: Lesch–Nyhan disease as a model disorder.Brain. 2014; 137: 1282-1303
- Delineation of the motor disorder of Lesch–Nyhan disease.Brain. 2006; 129: 1201-1217
- Neurocognitive functioning in Lesch–Nyhan disease and partial hypoxanthine-guanine phosphoribosyltransferase deficiency.J. Int. Neuropsychol. Soc. 2001; 7: 805-812
- Behavioral aspects in Lesch–Nyhan disease and its variants.Dev. Med. Child Neurol. 2005; 47: 673-677
- HPRT-deficient (Lesch–Nyhan) mouse embryos derived from germline colonization by cultured cells.Nature. 1987; 326: 292-295
- A potential animal model for Lesch–Nyhan syndrome through introduction of HPRT mutations into mice.Nature. 1987; 326: 295-298
- Behavioral and neurochemical evaluation of a transgenic mouse model of Lesch–Nyhan syndrome.J. Neurol. Sci. 1988; 86: 203-213
- Monoamine deficiency in a transgenic (Hprt-) mouse model of Lesch–Nyhan syndrome.Brain Res. 1989; 501: 401-406
- Amphetamine-induced behavioral phenotype in a hypoxanthine-guanine phosphoribosyltransferase-deficient mouse model of Lesch–Nyhan syndrome.Behav. Neurosci. 1991; 105: 1004-1012
- Functional analysis of brain dopamine systems in a genetic mouse model of Lesch–Nyhan syndrome.J. Pharmacol. Exp. Ther. 1992; 263: 596-607
- Localization of hypoxanthine-guanine phosphoribosyltransferase mRNA in the mouse brain by in situ hybridization.Mol. Cell. Neurosci. 1992; 3: 64-78
- Brain purines in a genetic mouse model of Lesch–Nyhan disease.J. Neurochem. 1993; 60: 2036-2045
- Dopamine deficiency in a genetic mouse model of Lesch–Nyhan disease.J. Neurosci. 1994; 14: 1164-1175
- Influence of age and strain on striatal dopamine loss in a genetic mouse model of Lesch–Nyhan disease.J. Neurochem. 1999; 72: 225-229
- Tetrahydrobiopterin deficiency and dopamine loss in a genetic mouse model of Lesch–Nyhan disease.J. Inherit. Metab. Dis. 2004; 27: 165-178
- A Golgi study of neuronal architecture in a genetic mouse model for Lesch–Nyhan disease.Neurobiol. Dis. 2005; 20: 479-490
- Basal ganglia dopamine loss due to defect in purine recycling.Neurobiol. Dis. 2007; 26: 396-407
- Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch–Nyhan syndrome.N. Engl. J. Med. 1981; 305: 1106-1111
- Dopamine receptor upregulation in Lesch–Nyhan syndrome: a postmortem study.Neuropediatrics. 1999; 30: 66-71
- Lesch–Nyhan disease and the basal ganglia.Brain Res. Brain Res. Rev. 2000; 32: 449-475
- Altered histamine neurotransmission in HPRT-deficient mice.Neurosci. Lett. 2015; 609: 74-80
- KEGG for integration and interpretation of large-scale molecular data sets.Nucleic Acids Res. 2012; 40: D109-D114
- The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases.Nucleic Acids Res. 2016; 44: D471-D480
- Development of neurotransmitter systems during critical periods.Exp. Neurol. 2004; 190: S8-21
- Effects of L-5-hydroxytryptophan on monoamine and amino acids turnover in the Lesch–Nyhan syndrome.J. Autism Dev. Disord. 1979; 9: 95-103
- Lesch–Nyhan syndrome: CSF neurotransmitter abnormalities.Neurology. 1985; 35: 907-911
- Lesch–Nyhan syndrome: a study of motor behavior and cerebrospinal fluid neurotransmitters.Ann. Neurol. 1988; 23: 466-469
- Lesch–Nyhan syndrome and its pathogenesis: purine concentrations in plasma and urine with metabolite profiles in CSF.J. Inherit. Metab. Dis. 1988; 11: 239-252
- Lesch–Nyhan syndrome with delayed onset of self-mutilation: hyperactivity of interneurons at the brainstem and blink reflex.Acta Neurol. Scand. 1990; 81: 184-187
- Behavioral differences between neonatal and adult 6-hydroxydopamine-treated rats to dopamine agonists: relevance to neurological symptoms in clinical syndromes with reduced brain dopamine.J. Pharmacol. Exp. Ther. 1984; 231: 343-354
- No self-injurious behavior was found in HPRT-deficient mice treated with 9-ethyladenine.Pharmacol. Biochem. Behav. 1998; 61: 175-179
Article info
Publication history
Published online: April 16, 2016
Accepted:
April 14,
2016
Received in revised form:
April 8,
2016
Received:
March 22,
2016
Identification
Copyright
© 2016 Elsevier B.V. All rights reserved.
