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
Molecular Neurobiology, Groningen Institute for Evolutionary Life Sciences, University of Groningen Groningen, Netherlands.
Department of Pediatrics, Beatrix Children's Hospital, University Medical Center Groningen Groningen, Netherlands.
Front Behav Neurosci. 2016 Dec 20;10:233. doi: 10.3389/fnbeh.2016.00233. eCollection 2016.
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.
为了弄清楚基因突变在健康和疾病状态下所起的作用，无数研究试图将基因型与表型联系起来。然而，多年来人们逐渐明白，小鼠的品系会影响这些结果。尽管如此，不同品系中相同的基因突变通常仍被视为等同。苯丙酮尿症（PKU）相关研究就是一个例子，苯丙酮尿症是一种遗传性代谢紊乱疾病。在这个领域，常使用PKU小鼠模型（背景为BTBR或C57Bl/6）来研究该疾病的潜在机制和/或新的治疗策略。两种品系在编码苯丙氨酸羟化酶的基因上都有一个点突变，这会导致血液和大脑中苯丙氨酸浓度达到有毒水平，PKU患者中也发现了这种情况。尽管突变相同，因此假定对两种品系的生理和行为影响相同，但尚无研究直接比较这两种遗传背景以验证这一假设。因此，本研究比较了BTBR和C57Bl/6野生型及PKU小鼠在与PKU相关的氨基酸和神经递质水平以及行为水平上的差异。行为范式是从先前关于PKU小鼠模型的文献中选取的，涉及四个方面，即（1）活动水平，（2）运动表现，（3）焦虑和/或抑郁样行为，以及（4）学习和记忆。本研究结果表明，苯丙氨酸和神经递质浓度的生化变化具有可比性。相比之下，在上述所有四个方面，两种品系的行为结果存在明显差异，最显著的是在学习和记忆方面。该方面的结果似乎主要归因于小鼠遗传背景固有的因素，而较少受血液和大脑中PKU特异性生化参数差异的影响。两种品系PKU行为结果的差异强调，苯丙氨酸羟化酶（PAH）突变的后果不仅受苯丙氨酸水平影响，还受其他因素影响。因此，未来研究在选择其中一种遗传品系来研究PKU相关行为的病理生理机制时，尤其是在结合新的治疗策略时，应考虑这些差异。
