Behavioral and Neurochemical Characterization of New Mouse Model of Hyperphenylalaninemia

Pascucci, Tiziana; Giacovazzo, Giacomo; Andolina, Diego; Accoto, Alessandra; Fiori, E.; Ventura, Rossella; Orsini, Cristina; Conversi, David; Carducci, Claudia; Leuzzi, Vincenzo; Puglisi-Allegra, Stefano

doi:10.1371/journal.pone.0084697

Cited by 17 publications

(20 citation statements)

References 36 publications

(42 reference statements)

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“…Both strains showed a vast increase in Phe levels and disrupted serotonin and norepinephrine levels in the brain (for norepinephrine a trend was observed for BTBR statistically) which is in accordance with previous studies (Andolina et al, 2011; Pascucci et al, 2013; Sawin et al, 2014; van Vliet et al, 2015). How these PKU-related changes can result in a different functional outcome is not clear.…”

Section: Discussionsupporting

confidence: 91%

The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

Bruinenberg

Goot

Vliet

et al. 2016

Front. Behav. Neurosci.

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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.

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Section: Discussionsupporting

confidence: 91%

The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

Bruinenberg

Goot

Vliet

et al. 2016

Front. Behav. Neurosci.

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“…In addition, distance moved and velocity during the Open Field Test showed that 18-day-old ENU2 pups had lower general activity than age-matched WT. These data are in agreement with several previous studies showing reduced locomotor activity in adult animal model of PKU [ 24 , 34 , 35 , 43 ] and underline the precociousness of the deficit.…”

Section: Discussionsupporting

confidence: 93%

“…This result is in line with several reports suggesting that growth in early childhood in PKU is reduced in comparison with reference populations [ 44 ], as well as with a previous preclinical report showing reduced postnatal growth in ENU2 mice in comparison with heterozygous littermates [ 45 ]. It should be noted that, although heterozygous ENU2 mice have been often used as control group instead of WT subjects, abolishing the costs of genetic characterization following heterozygous mating, recent data have confirmed hyperphenylalaninemic status of heterozygous ENU2 mice [ 24 ]. Therefore, the use of heterozygous mice as control group is questioned.…”

Section: Discussionmentioning

confidence: 99%

“…The development and the study of new treatments take advantage of preclinical models, the most used of which is the PAH enu2 (ENU2), the genetic murine model of PKU. The chemically induced genetic mutation [ 15 ] in the chromosome coding for PAH in this model results in a phenotype closely resembling untreated human PKU, being characterized by reduced PAH activity, PHE plasma levels 10–20 times higher than those of healthy littermates, hypomyelination, behavioral and neurochemical deficits [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, to the best of knowledge, no data are available on the behavioral phenotype of ENU2 mice during early postnatal life, as studies focused on adult animals [ 16 , 23 , 24 , 27 , 28 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

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Early-onset behavioral and neurochemical deficits in the genetic mouse model of phenylketonuria

et al. 2017

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Phenylketonuria (PKU) is one of the most common human inborn errors of metabolism, caused by phenylalanine hydroxylase deficiency, leading to high phenylalanine and low tyrosine levels in blood and brain causing profound cognitive disability, if untreated. Since 1960, population is screened for hyperphenylalaninemia shortly after birth and submitted to early treatment in order to prevent the major manifestations of the disease. However, the dietetic regimen (phenylalanine free diet) is difficult to maintain, and despite the recommendation to a strict and lifelong compliance, up to 60% of adolescents partially or totally abandons the treatment. The development and the study of new treatments continue to be sought, taking advantage of preclinical models, the most used of which is the PAHenu2 (BTBR ENU2), the genetic murine model of PKU. To date, adult behavioral and neurochemical alterations have been mainly investigated in ENU2 mice, whereas there are no clear indications about the onset of these deficiencies. Here we investigated and report, for the first time, a comprehensive behavioral and neurochemical assay of the developing ENU2 mice. Overall, our findings demonstrate that ENU2 mice are significantly smaller than WT until pnd 24, present a significant delay in the acquisition of tested developmental reflexes, impaired communicative, motor and social skills, and have early reduced biogenic amine levels in several brain areas. Our results extend the understanding of behavioral and cerebral abnormalities in PKU mice, providing instruments to an early preclinical evaluation of the effects of new treatments.

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Oral administration of phenylalanine molecularly imprinted polymer (MIP) benefits PKU mouse model

Torab

Jafari‐Sabet

Najafizadeh

et al. 2022

J of Inher Metab Disea

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Phenylketonuria (PKU) is a rare genetic disorder caused by a defect in the metabolism of phenylalanine (Phe). Currently, the most commonly used treatment for PKU is dietary Phe restriction. Problems associated with Phe restricted diets include lack of universal availability, high treatment costs, and reduced adherence to continued treatment with age and finally the development of psychological and neurological problems in a significant proportion of patients despite early start of treatment. One possible approach to decreasing blood Phe level, is inhibition of GI tract absorption of this amino acid. We had previously shown that a Phe selective molecularly imprinted polymer was able to bind Phe in the GI tract and attenuate its plasma concentration. In this work, we used different orally administered Phe selective molecularly imprinted polymer doses in a PKU mouse model to further study the effects of this treatment on biochemical profile and cognitive function in test animals. Treatments started 21 days postnatally. After 3 weeks, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Behavioral profile was also evaluated. Treatment with 2% and 5% Phe selective molecularly imprinted polymer significantly reduced levels of blood Phe in PKU model animals (46% and 48% respectively) meanwhile levels of other amino acids remained unchanged. Brain dopamine concentrations in hippocampus was effectively restored by supplementation of Phe selective molecularly imprinted polymer. Finally, polymer treatment improved locomotor dysfunction in PKU model animals. Our data suggest that the Phe selective molecularly imprinted polymer can be a new candidate for treatment of PKU patients. Take home message: Orally administered Phenylalanine Selective Molecularly Imprinted Polymer is able to inhibit absorption of phenylalanine from the GI tract and may offer a new treatment, in conjunction with dietary restriction, for PKU patients.

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Behavioral and Neurochemical Characterization of New Mouse Model of Hyperphenylalaninemia

Cited by 17 publications

References 36 publications

The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

Early-onset behavioral and neurochemical deficits in the genetic mouse model of phenylketonuria

Oral administration of phenylalanine molecularly imprinted polymer (MIP) benefits PKU mouse model

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