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cAMP/PKA-CREB-BDNF signaling pathway in hippocampus of rats subjected to chemically-induced phenylketonuria

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Abstract

Phenylketonuria (PKU) is an inborn error disease in phenylalanine metabolism resulting from defects in the stages of converting phenylalanine to tyrosine. Although the pathophysiology of PKU is not elucidated yet, the toxic effect of phenylalanine on the brain causes severe mental retardation. In relation to learning and memory, the hippocampal PKA / CREB / BDNF pathway may play a role in learning deficits in PKU patients. This study aimed to investigate PKA/CREB/BDNF pathway in hippocampus of chemically induced PKU rats with regard to gender. Sprague-Dawley rat pups were randomized into two groups of both genders. To chemically induce PKU, animals received subcutaneous administration of phenylalanine (5.2 mmol / g) plus p-chlorophenylalanine, phenylalanine hydroxylase inhibitor (0.9 mmol / g); control animals received 0.9% NaCl. Injections started on the 6th day and continued until the 21st day after which locomotor activity, learning and memory were tested. In male PKU rats, locomotor activity was reduced. There were no differences in learning and memory performances of male and female PKU rats. In PKU rats, pCREB / CREB levels in males was unchanged while it decreased in females. Elevated PKA activity, BDNF levels and decreased pCREB/CREB ratio found in female PKU rats were not replicated in PKU males in which BDNF is decreased. Our results display that in this disease model a gender specific differential activation of cAMP/PKA-CREB-BDNF signaling pathway in hippocampus occurs investigation of which can help us to a better understanding of disease pathophysiology.

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Data availability

The authors declare that the data supporting the findings of this study are available in this published article.

Abbreviations

PKU:

phenylketonuria

PKA:

Protein Kinase A

BDNF:

brain derived neurotrophic factor

CREB:

cAMP response element binding protein

p-Cl-Phe:

p-chloro-phenylalanine

References

  • Akkerman S, Blokland A, Reneerkens O, van Goethem NP, Bollen E, Gijselaers HJ et al (2012) Object recognition testing: methodological considerations on exploration and discrimination measures. Behav Brain Res 232(2):335–347. https://doi.org/10.1016/j.bbr.2012.03.022

    Article  PubMed  Google Scholar 

  • Anderson PJ, Leuzzi V (2010) White matter pathology in phenylketonuria. Mol Genet Metab 99:S3–S9

    CAS  PubMed  Google Scholar 

  • Antunes M, Biala G (2012) The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process 13(2):93–110. https://doi.org/10.1007/s10339-011-0430-z

    Article  CAS  PubMed  Google Scholar 

  • Ardais AP, Rocha AS, Borges MF, Fioreze GT, Sallaberry C, Mioranzza S et al (2016) Caffeine exposure during rat brain development causes memory impairment in a sex selective manner that is offset by caffeine consumption throughout life. Behav Brain Res 303:76–84

    CAS  PubMed  Google Scholar 

  • Barco A, Bailey CH, Kandel ER (2006) Common molecular mechanisms in explicit and implicit memory. J Neurochem 97(6):1520–1533

    CAS  PubMed  Google Scholar 

  • Benito E, Barco A (2010) CREB’s control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models. Trends Neurosci 33(5):230–240

    CAS  PubMed  Google Scholar 

  • Berry HK, O'Grady DJ, Perlmutter LJ, Bofinger MK (1979) Intellectual development and academic achievement of children treated early for phenylketonuria. Developmental Medicine & Child Neurology 21(3):311–320

    CAS  Google Scholar 

  • Blau N, van Spronsen FJ, Levy HL (2010) Phenylketonuria. Lancet 376(9750):1417–1427

    CAS  PubMed  Google Scholar 

  • Bortoluzzi VT, Brust L, Preissler T, de Franceschi ID, Wannmacher CMD (2019) Creatine plus pyruvate supplementation prevents oxidative stress and phosphotransfer network disturbances in the brain of rats subjected to chemically-induced phenylketonuria. Metab Brain Dis 34(6):1649–1660. https://doi.org/10.1007/s11011-019-00472-7

    Article  CAS  PubMed  Google Scholar 

  • Bronstein PM, Wolkoff FD, Levine MJ (1975) Sex-related differences in rats' open-field activity. Behav Biol

  • Bruinenberg VM, van der Goot E, van Vliet D, de Groot MJ, Mazzola PN, Heiner-Fokkema MR et al (2016) The behavioral consequence of phenylketonuria in mice depends on the genetic background. Front Behav Neurosci 10:233

    PubMed  PubMed Central  Google Scholar 

  • Burlina AP, Lachmann RH, Manara R, Cazzorla C, Celato A, van Spronsen FJ, Burlina A (2019) The neurological and psychological phenotype of adult patients with early-treated phenylketonuria: a systematic review. J Inherit Metab Dis 42(2):209–219

    PubMed  Google Scholar 

  • Christ SE, Huijbregts SC, de Sonneville LM, White DA (2010) Executive function in early-treated phenylketonuria: profile and underlying mechanisms. Mol Genet Metab 99:S22–S32

    CAS  PubMed  Google Scholar 

  • de Groot MJ, Hoeksma M, Reijngoud D-J, de Valk HW, Paans AM, Sauer PJ, van Spronsen FJ (2013) Phenylketonuria: reduced tyrosine brain influx relates to reduced cerebral protein synthesis. Orphanet J Rare Dis 8(1):133

    PubMed  PubMed Central  Google Scholar 

  • de Sousa Abreu R, Penalva LO, Marcotte EM, Vogel C (2009) Global signatures of protein and mRNA expression levels. Mol BioSyst 5(12):1512–1526

    PubMed  Google Scholar 

  • Delvalle JA, Dienel G, Greengard O (1978) Comparison of α-methylphenylalanine and p-chlorophenylalanine as inducers of chronic hyperphenylalaninaemia in developing rats. Biochem J 170(3):449–459

    CAS  PubMed  PubMed Central  Google Scholar 

  • Delvalle JA, Greengard O (1976) The regulation of phenylalanine hydroxylase in rat tissues in vivo. The maintenance of high plasma phenylalanine concentrations in suckling rats: a model for phenylketonuria. Biochem J 154(3):613–618

    CAS  PubMed  PubMed Central  Google Scholar 

  • Diamond A, Ciaramitaro V, Donner E, Djali S, Robinson MB (1994) An animal model of early-treated PKU. J Neurosci 14(5):3072–3082

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dienel GA, Cruz NF (2016) Biochemical, metabolic, and behavioral characteristics of immature chronic hyperphenylalanemic rats. Neurochem Res 41(1–2):16–32

    CAS  PubMed  Google Scholar 

  • Dimer NW, Ferreira BK, Agostini JF, Gomes ML, Kist LW, Malgarin F et al (2018) Brain bioenergetics in rats with acute hyperphenylalaninemia. Neurochem Int 117:188–203. https://doi.org/10.1016/j.neuint.2018.01.001

    Article  CAS  PubMed  Google Scholar 

  • Enns G, Koch R, Brumm V, Blakely E, Suter R, Jurecki E (2010) Suboptimal outcomes in patients with PKU treated early with diet alone: revisiting the evidence. Mol Genet Metab 101(2–3):99–109

    CAS  PubMed  Google Scholar 

  • Fiori E, Oddi D, Ventura R, Colamartino M, Valzania A, D’Amato FR et al (2017) Early-onset behavioral and neurochemical deficits in the genetic mouse model of phenylketonuria. PLoS One 12(8):e0183430

    PubMed  PubMed Central  Google Scholar 

  • Graves LM, Bornfeldt KE, Raines EW, Potts BC, Macdonald SG, Ross R, Krebs EG (1993) Protein kinase a antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proc Natl Acad Sci 90(21):10300–10304

    CAS  PubMed  PubMed Central  Google Scholar 

  • Grimes MT, Harley CW, Darby-King A, McLean JH (2012) PKA increases in the olfactory bulb act as unconditioned stimuli and provide evidence for parallel memory systems: pairing odor with increased PKA creates intermediate-and long-term, but not short-term, memories. Learn Mem 19(3):107–115

    CAS  PubMed  Google Scholar 

  • Guo J-Q, Deng H-H, Bo X, Yang X-S (2017) Involvement of BDNF/TrkB and ERK/CREB axes in nitroglycerin-induced rat migraine and effects of estrogen on these signals in the migraine. Biology open 6(1):8–16

    CAS  PubMed  Google Scholar 

  • Impey S, Obrietan K, Wong ST, Poser S, Yano S, Wayman G et al (1998) Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21(4):869–883. https://doi.org/10.1016/S0896-6273(00)80602-9

    Article  CAS  PubMed  Google Scholar 

  • Jahan S, Singh S, Srivastava A, Kumar V, Kumar D, Pandey A et al (2018) PKA-GSK3β and β-catenin signaling play a critical role in trans-resveratrol mediated neuronal differentiation in human cord blood stem cells. Mol Neurobiol 55(4):2828–2839

    CAS  PubMed  Google Scholar 

  • Jahja R, Huijbregts SC, de Sonneville LM, van der Meere JJ, Bosch AM, Hollak CE et al (2013) Mental health and social functioning in early treated phenylketonuria: the PKU-COBESO study. Mol Genet Metab 110:S57–S61

    CAS  PubMed  Google Scholar 

  • Jahja R, van Spronsen FJ, de Sonneville LM, van der Meere JJ, Bosch AM, Hollak CE et al (2016) Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study. J Inherit Metab Dis 39(3):355–362

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jain A, Huang GZ, Woolley CS (2019) Latent sex differences in molecular signaling that underlies excitatory synaptic potentiation in the Hippocampus. J Neurosci 39(9):1552–1565. https://doi.org/10.1523/jneurosci.1897-18.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janzen D, Nguyen M (2010) Beyond executive function: non-executive cognitive abilities in individuals with PKU. Mol Genet Metab 99:S47–S51

    CAS  PubMed  Google Scholar 

  • Jiang, H, Zhang, X, Wang, Y, Zhang, H, Li, J, Yang, X, . . . Xu, M (2017) Mechanisms underlying the antidepressant response of acupuncture via PKA/CREB signaling pathway. Neural plasticity, 2017

  • Kandel ER (2012) The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Molecular brain 5(1):1–12

    Google Scholar 

  • Konkle AT, McCarthy MM (2011) Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain. Endocrinology 152(1):223–235

    CAS  PubMed  Google Scholar 

  • Leal G, Bramham C, Duarte C (2017) BDNF and hippocampal synaptic plasticity. In vitamins and hormones, vol 104. Elsevier, pp 153–195

    Google Scholar 

  • Liu F, Liu Y, Liu J, Ma L-Y (2015) Antenatal taurine improves intrauterine growth-restricted fetal rat brain development which is associated with increasing the activity of PKA-CaMKII/c-fos signal pathway. Neuropediatrics 46(05):299–306

    PubMed  Google Scholar 

  • Lu L, Gu X, Li D, Liang L, Zhao Z, Gao J (2011) Mechanisms regulating superoxide generation in experimental models of phenylketonuria: an essential role of NADPH oxidase. Mol Genet Metab 104(3):241–248

    CAS  PubMed  Google Scholar 

  • Maier T, Güell M, Serrano L (2009) Correlation of mRNA and protein in complex biological samples. FEBS Lett 583(24):3966–3973

    CAS  PubMed  Google Scholar 

  • Martynyuk A, Glushakov A, Sumners C, Laipis P, Dennis D, Seubert C (2005) Impaired glutamatergic synaptic transmission in the PKU brain. Mol Genet Metab 86:34–42

    Google Scholar 

  • Nardecchia F, Manti F, Chiarotti F, Carducci C, Carducci C, Leuzzi V (2015) Neurocognitive and neuroimaging outcome of early treated young adult PKU patients: a longitudinal study. Mol Genet Metab 115(2–3):84–90

    CAS  PubMed  Google Scholar 

  • Ögren SO, Stiedl O (2010) Passive Avoidance. In: Stolerman IP (ed) Encyclopedia of psychopharmacology. Springer Berlin Heidelberg, Berlin, Heidelberg, pp 960–967

    Google Scholar 

  • Parks RJ, Ray G, Bienvenu LA, Rose RA, Howlett SE (2014) Sex differences in SR Ca2+ release in murine ventricular myocytes are regulated by the cAMP/PKA pathway. J Mol Cell Cardiol 75:162–173

    CAS  PubMed  Google Scholar 

  • Rao X, Huang X, Zhou Z, Lin X (2013) An improvement of the 2ˆ(−delta delta CT) method for quantitative real-time polymerase chain reaction data analysis. Biostatistics, bioinformatics and biomathematics 3(3):71–85

    PubMed  PubMed Central  Google Scholar 

  • Rech VC, Feksa LR, Dutra-Filho CS, Wyse AT, Wajner M, Wannmacher CM (2002) Inhibition of the mitochondrial respiratory chain by phenylalanine in rat cerebral cortex. Neurochem Res 27(5):353–357. https://doi.org/10.1023/a:1015529511664

    Article  CAS  PubMed  Google Scholar 

  • Sakamoto K, Karelina K, Obrietan K (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116(1):1–9

    CAS  PubMed  Google Scholar 

  • Simon KR, dos Santos RM, Scaini G, Leffa DD, Damiani AP, Furlanetto CB et al (2013) DNA damage induced by phenylalanine and its analogue p-chlorophenylalanine in blood and brain of rats subjected to a model of hyperphenylalaninemia. Biochem Cell Biol 91(5):319–324

    CAS  PubMed  Google Scholar 

  • Surtees R, Blau N (2000) The neurochemistry of phenylketonuria. Eur J Pediatr 159(2):S109–S113

    CAS  PubMed  Google Scholar 

  • van Spronsen FJ, van Wegberg AM, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM et al (2017) Key European guidelines for the diagnosis and management of patients with phenylketonuria. The lancet Diabetes & endocrinology 5(9):743–756

    Google Scholar 

  • Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 13(4):227–232

    CAS  PubMed  PubMed Central  Google Scholar 

  • Vrolyk V, Haruna J, Benoit-Biancamano MO (2018) Neonatal and juvenile ocular development in Sprague-Dawley rats: a Histomorphological and Immunohistochemical study. Vet Pathol 55(2):310–330. https://doi.org/10.1177/0300985817738098

    Article  CAS  PubMed  Google Scholar 

  • Zhong Y, Zhu Y, He T, Li W, Yan H, Miao Y (2016) Rolipram-induced improvement of cognitive function correlates with changes in hippocampal CREB phosphorylation, BDNF and arc protein levels. Neurosci Lett 610:171–176

    CAS  PubMed  Google Scholar 

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Funding

This work was funded from Hacettepe University Grant No: TDK-2018-16969 to E.B and by TUBİTAK 2214-A International Research Fellowship Program to C.C.

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Authors and Affiliations

  1. Department of Medical Biochemistry, Hacettepe University, Faculty of Medicine, 06100, Ankara, Turkey

    Cigdem Cicek, Muslum Gok & Ebru Bodur

  2. Department of Medical Biochemistry, Yuksek Ihtisas University, Faculty of Medicine, 06520, Ankara, Turkey

    Cigdem Cicek

  3. Hacettepe University, Institute of Neurological Sciences and Psychiatry, 06100, Ankara, Turkey

    Emine Eren-Koçak

  4. Department of Medical Biology, Yuksek Ihtisas University, Faculty of Medicine, 06520, Ankara, Turkey

    Pelin Telkoparan-Akillilar

  5. Department of Medical Biochemistry, Mugla Sitki Kocman University, Faculty of Medicine, 48000, Mugla, Turkey

    Muslum Gok

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  1. Cigdem Cicek
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  2. Emine Eren-Koçak
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  3. Pelin Telkoparan-Akillilar
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  4. Muslum Gok
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Contributions

EB and ÇÇ conceived the study; EB and EEK supervised the study; EB and EEK designed experiments; ÇÇ, PTA and MG performed experiments; EEK, PTA and EB analyzed data; EB, ÇÇ and EEK wrote the manuscript; PTA and MG made manuscript revisions. All authors reviewed the results and approved the final version of the manuscript.

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Correspondence to Ebru Bodur.

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All experimental procedures were designed to minimize the number of animals used and their suffering and were approved by Hacettepe University Committee on Animal Ethics (Protocol No 2018/02–12).

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Cicek, C., Eren-Koçak, E., Telkoparan-Akillilar, P. et al. cAMP/PKA-CREB-BDNF signaling pathway in hippocampus of rats subjected to chemically-induced phenylketonuria. Metab Brain Dis 37, 545–557 (2022). https://doi.org/10.1007/s11011-021-00865-7

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