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The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background
To unravel the role of gene mutations in the healthy and the diseased state, countless studies have tried to link genotype with phenotype. However, over the years, it became clear that the strain of mice can influence these results. Nevertheless, identical gene mutations in different strains are oft...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167755/ https://www.ncbi.nlm.nih.gov/pubmed/28066199 http://dx.doi.org/10.3389/fnbeh.2016.00233 |
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author | Bruinenberg, Vibeke M. van der Goot, Els van Vliet, Danique de Groot, Martijn J. Mazzola, Priscila N. Heiner-Fokkema, M. Rebecca van Faassen, Martijn van Spronsen, Francjan J. van der Zee, Eddy A. |
author_facet | Bruinenberg, Vibeke M. van der Goot, Els van Vliet, Danique de Groot, Martijn J. Mazzola, Priscila N. Heiner-Fokkema, M. Rebecca van Faassen, Martijn van Spronsen, Francjan J. van der Zee, Eddy A. |
author_sort | Bruinenberg, Vibeke M. |
collection | PubMed |
description | To unravel the role of gene mutations in the healthy and the diseased state, countless studies have tried to link genotype with phenotype. However, over the years, it became clear that the strain of mice can influence these results. Nevertheless, identical gene mutations in different strains are often still considered equals. An example of this, is the research done in phenylketonuria (PKU), an inheritable metabolic disorder. In this field, a PKU mouse model (either on a BTBR or C57Bl/6 background) is often used to examine underlying mechanisms of the disease and/or new treatment strategies. Both strains have a point mutation in the gene coding for the enzyme phenylalanine hydroxylase which causes toxic concentrations of the amino acid phenylalanine in blood and brain, as found in PKU patients. Although the mutation is identical and therefore assumed to equally affect physiology and behavior in both strains, no studies directly compared the two genetic backgrounds to test this assumption. Therefore, this study compared the BTBR and C57Bl/6 wild-type and PKU mice on PKU-relevant amino acid- and neurotransmitter-levels and at a behavioral level. The behavioral paradigms were selected from previous literature on the PKU mouse model and address four domains, namely (1) activity levels, (2) motor performance, (3) anxiety and/or depression-like behavior, and (4) learning and memory. The results of this study showed comparable biochemical changes in phenylalanine and neurotransmitter concentrations. In contrast, clear differences in behavioral outcome between the strains in all four above-mentioned domains were found, most notably in the learning and memory domain. The outcome in this domain seem to be primarily due to factors inherent to the genetic background of the mouse and much less by differences in PKU-specific biochemical parameters in blood and brain. The difference in behavioral outcome between PKU of both strains emphasizes that the consequence of the PAH mutation is influenced by other factors than Phe levels alone. Therefore, future research should consider these differences when choosing one of the genetic strains to investigate the pathophysiological mechanism underlying PKU-related behavior, especially when combined with new treatment strategies. |
format | Online Article Text |
id | pubmed-5167755 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-51677552017-01-06 The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background Bruinenberg, Vibeke M. van der Goot, Els van Vliet, Danique de Groot, Martijn J. Mazzola, Priscila N. Heiner-Fokkema, M. Rebecca van Faassen, Martijn van Spronsen, Francjan J. van der Zee, Eddy A. Front Behav Neurosci Neuroscience To unravel the role of gene mutations in the healthy and the diseased state, countless studies have tried to link genotype with phenotype. However, over the years, it became clear that the strain of mice can influence these results. Nevertheless, identical gene mutations in different strains are often still considered equals. An example of this, is the research done in phenylketonuria (PKU), an inheritable metabolic disorder. In this field, a PKU mouse model (either on a BTBR or C57Bl/6 background) is often used to examine underlying mechanisms of the disease and/or new treatment strategies. Both strains have a point mutation in the gene coding for the enzyme phenylalanine hydroxylase which causes toxic concentrations of the amino acid phenylalanine in blood and brain, as found in PKU patients. Although the mutation is identical and therefore assumed to equally affect physiology and behavior in both strains, no studies directly compared the two genetic backgrounds to test this assumption. Therefore, this study compared the BTBR and C57Bl/6 wild-type and PKU mice on PKU-relevant amino acid- and neurotransmitter-levels and at a behavioral level. The behavioral paradigms were selected from previous literature on the PKU mouse model and address four domains, namely (1) activity levels, (2) motor performance, (3) anxiety and/or depression-like behavior, and (4) learning and memory. The results of this study showed comparable biochemical changes in phenylalanine and neurotransmitter concentrations. In contrast, clear differences in behavioral outcome between the strains in all four above-mentioned domains were found, most notably in the learning and memory domain. The outcome in this domain seem to be primarily due to factors inherent to the genetic background of the mouse and much less by differences in PKU-specific biochemical parameters in blood and brain. The difference in behavioral outcome between PKU of both strains emphasizes that the consequence of the PAH mutation is influenced by other factors than Phe levels alone. Therefore, future research should consider these differences when choosing one of the genetic strains to investigate the pathophysiological mechanism underlying PKU-related behavior, especially when combined with new treatment strategies. Frontiers Media S.A. 2016-12-20 /pmc/articles/PMC5167755/ /pubmed/28066199 http://dx.doi.org/10.3389/fnbeh.2016.00233 Text en Copyright © 2016 Bruinenberg, van der Goot, van Vliet, de Groot, Mazzola, Heiner-Fokkema, van Faassen, van Spronsen and van der Zee. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Bruinenberg, Vibeke M. van der Goot, Els van Vliet, Danique de Groot, Martijn J. Mazzola, Priscila N. Heiner-Fokkema, M. Rebecca van Faassen, Martijn van Spronsen, Francjan J. van der Zee, Eddy A. The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background |
title | The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background |
title_full | The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background |
title_fullStr | The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background |
title_full_unstemmed | The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background |
title_short | The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background |
title_sort | behavioral consequence of phenylketonuria in mice depends on the genetic background |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5167755/ https://www.ncbi.nlm.nih.gov/pubmed/28066199 http://dx.doi.org/10.3389/fnbeh.2016.00233 |
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