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The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH-5 mouse brain

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Journal of Inherited Metabolic Disease

Summary

Previous studies on the effect of hyperphenylalaninaemia on the development of the muscarinic acetylcholine receptor in the cerebrum of the rat, using α-methylphenylalanine-induced hyperphenylalaninaemia, have shown a gradual and steady decrease in the number of binding sites for this neurotransmitter. The HPH-5 mouse, a phenylalanine hydroxylase mutant, can be hyperphenylalaninaemic without the use of a hydroxylase inhibitor. By employing quantitative autoradiography using [3H]quinuclinidylbenzilate to label muscarinic acetylcholine receptors, a refined analysis of this decrease in neurotransmitter binding sites can be made. The decrease was confirmed and is therefore due to the hyperphenylalaninaemiaper se and not to the use of the inhibitor. Various areas of the brain reacted differently to hyperphenylalaninaemia, from no change (putamen) to a gradual decrease (external layer of the olfactory bulb, parietal, occipital and cingulate areas of the cerebral cortex, CA1 and CA3 layer of the hippocampus) to a decrease preceded by a transient increase (frontal area of the cerebral cortex, caudate nucleus).

The extent of these changes depends on the duration of exposure to hyperphenylalaninaemia as well as on the degree of brain maturation, but can even be observed in the brain of the adult mouse on a hyperphenylalaninaemic regimen for 11 days.

Since the hippocampus has been shown to be involved in the long-term storage of information, damage to this structure by hyperphenylalaninaemia may provide a clue to the global mental retardation observed in untreated PKU.

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References

  • Alvord EC, Stevenson LD, Vogel FS, Engle RL (1950) Neuropathological findings in phenylpyruvic oligophrenia (phenylketonuria).J Neuropath Exp Neurol 9: 298–310.

    Google Scholar 

  • Baumann LL, Kemper TL (1982) Morphological and histoanatomical observations of the brain in untreated human phenylketonuria.Acta Neuropathol 58: 55–63.

    Google Scholar 

  • Berger R, Springer J, Hommes FA (1980) Brain protein and myelin metabolism in young hyperphenylalaninemic rats.Moll Cell Biol 26: 31–36.

    Google Scholar 

  • Bick U, Fahrendorf G, Ludolph AC, Vasallo P, Weglage J, Ullrich K (1991) Disturbed myelination in patients with treated hyperphenylalaninemia: evaluation with magnetic resonance imaging.Eur J Pediatr 150: 185–189.

    Google Scholar 

  • Bonner TJ, Buckley NJ, Young AC, Braun MR (1987) Identification of a family of muscarinic acetylcholine receptor genes.Science 237: 527–532.

    Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.Anal Biochem 72: 248–254.

    Google Scholar 

  • Crome L (1962) The association of phenylketonuria with leukodystrophy.J Neurol Neurosurg Psychiatr 25: 149–153.

    Google Scholar 

  • Dias-Granadas YL, Amsch A (1992) Memory based learning in preweanling and adult rats after infantile X-irradiation-induced hippocampal granule cell hypoplasia.Behav Neurosci 106: 940–946.

    Google Scholar 

  • Eichenbaum H, Mathews P, Cohen NJ (1989) Further studies of hippocampal representation during odor determination learning.Behav Neurol Sci 103: 1207–1216.

    Google Scholar 

  • Gaull GE, Tallan HH, Lajtha A, Rassin DK (1975) Pathogenesis of brain dysfunction in inborn errors of amino acid metabolism. In Gaull GE, ed.Biology of Brain Dysfunction. New York: Plenum, vol. 3, 47–143.

    Google Scholar 

  • Geary WA, Toga AW, Wooten GF (1985) Quantitative film autoradiography for tritium: Methodological considerations.Brain Res 337: 99–108.

    Google Scholar 

  • Getting PA (1989) Emerging principles governing the operation of neuronal networks.Annu Rev Neurosci 12: 185–204.

    Google Scholar 

  • Harrison PJ, Barton AJL, Najlerahim A, McDonald B, Pearson RCA (1991) Increased muscarinic receptor messenger RNA in Alzheimer's disease temporal cortex demonstrated byin situ hybridization histochemistry.Mol Brain Res 9: 15–21.

    Google Scholar 

  • Herkenham M (1987) Mismatches between neurotransmitter and receptor localizations in brain: observations and implications.Neurosci 23: 1–38.

    Google Scholar 

  • Herkenham M, Sokoloff L (1984) Quantitative receptor autoradiography: Tissue defatting eliminates differential self-absorption of tritium radiation in gray and white matter of brain.Brain Res 321: 363–368.

    Google Scholar 

  • Hommes FA (1985) Myelin turnover at later stages of brain development in experimental hyperphenylalaninemia. In Bickel H, Wachtel U, eds.Inherited Diseases of Amino Acid Metabolism. Stuttgart: Thieme Verlag, 67–85.

    Google Scholar 

  • Hommes FA (1991) On the mechanism of permanent brain dysfunction in hyperphenylalaninemia.Biochem Med Metab Biol 46: 277–287.

    Google Scholar 

  • Hommes FA (1993) The effect of hyperphenylalaninemia on the muscarinic acetylcholine receptor of the HPH-5 mouse. Abstr 3rd Annu Miami Childr Hosp Res Inst Symp Intern Pediatr,8: 141.

    Google Scholar 

  • Hommes FA, Matsuo K (1987) On a possible mechanism of abnormal brain development in experimental hyperphenylalaninemia.Neurochem Int 11: 1–10.

    Google Scholar 

  • Hommes FA, Matsuo K (1988) Effect of phenylalanine on brain maturation: Implications for the treatment of patients with phenylektonuria. In Wurtman RJ, Ritter-Walker E, eds.Dietary Phenylalanine and Brain Function. Boston: Birkhauser, 238–243.

    Google Scholar 

  • Hommes FA, Moss L (1992) Myelin turnover in hyperphenylalaninemia. A re-evaluation with the HPH-5 mouse.J Inher Metab Dis 15: 243–251.

    Google Scholar 

  • Hommes FA, Eller AG, Taylor EH (1982) Turnover of the fast component of myelin and myelin proteins in experimental hyperphenylalaninemia. Relevance to termination of dietary treatment in human PKU.J Inher Metab Dis 5: 21–27.

    Google Scholar 

  • Huttenlocher PR, de Courten Ch (1987) The development of synapses in striate cortex of man.Human Neurobiol 6: 1–9.

    Google Scholar 

  • Jervis GA (1954) Phenylpyruvic oligophrenia (phenylketonuria).Res Publ Assoc Res New Ment Dis 33: 259–282.

    Google Scholar 

  • Kornguth S, Gilbert-Barness E, Langer E, Hegstrand L (1992) Golgi-Kopsch silver study of the brain of a patient with untreated phenylketonuria, seizures, and cortical blindness.Am J Med Genet 44: 443–448.

    Google Scholar 

  • Kuhar MJ (1985) Receptor localization with the microscope. In Yamamura HJ, ed.Neurotransmitter Receptor Binding. New York: Raven Press, 153–176.

    Google Scholar 

  • Kuhar MJ, Yamamura HI (1975) Light autoradiographic localization of cholinergic muscarinic receptors in rat brain by specific binding of a patent antagonist.Nature 253: 650–651.

    Google Scholar 

  • Kuhar MJ, Yamamura HI (1976) Localization of cholinergic muscarinic receptors in rat brain by light microscopic radioautography.Brain Res 110: 229–243.

    Google Scholar 

  • Lou HC, Toft PB, Andrese J et al (1992) An occipital-temporal syndrome in adolescents with optimally controlled hyperphenylalaninemia.J Inher Metab Dis 15: 687–695.

    Google Scholar 

  • Madison DV, Malenka RC, Nicoll RA (1991) Mechanisms underlying long-term potentiation of synaptic transmission.Annu Rev Neurosci 14: 379–397.

    Google Scholar 

  • Malamud N (1966) Neuropathology of phenylketonuria.J Neuropathol Exp Neurol 25: 254–268.

    Google Scholar 

  • Matsuo K, Hommes FA (1988) The development of the muscarinic acetylcholine receptor in normal and hyperphenylalaninemic rat cerebrum.Neurochem Res 13: 867–870.

    Google Scholar 

  • McDonald JD, Bode VC, Dove WF, Shedlovsky A (1990) PahHPH_5: A mouse mutant deficient in phenylalanine hydroxylase.Proc Natl Acad Sci USA 84: 1967–1969.

    Google Scholar 

  • McKinney M, Robbins M (1992) Chronic atropine administration up-regulates rat cortical muscarinic m1 receptor mRNA molecules: assessment with the RT/PCR.Brain Res Mol Brain Res 12: 39–45.

    Google Scholar 

  • Milner B, Corkin S, Teuber HL (1968) Further analysis of the hippocampal amnesic syndrome: 14-year follow-up study of H.M.Neuropsychologia 6: 215–234.

    Google Scholar 

  • Morris RGM, Garrud P, Rawlins JNP, O'Keefe J (1982) Place navigations impaired in rats with hippocampal lesions.Nature 297: 681–683.

    Google Scholar 

  • Parkinson JK, Murray EA, Mishkin M (1988) A selective mnemonic role for the hippocampus in monkeys: Memory for the location of objects.J Neurosci 8: 4159–4167.

    Google Scholar 

  • Pauly JR, Marks MJ, Gross SD, Collins AC (1991) An autoradiographic analysis of cholinergic receptors in mouse brain after chronic nicotine treatment.J Pharmacol Exp Ther 258: 1127–1136.

    Google Scholar 

  • Pearsen KD, Gean-Marton AD, Levy HL, Davis KR (1990) Phenylketonuria: MRI imaging of the brain with clinical correlation.Radiology 177: 437–440.

    Google Scholar 

  • Peralta MG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capan DJ (1987) Distinct primary structures, ligand binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors.EMBO J 6: 3923–3929.

    Google Scholar 

  • Poser CM, Van Bogaert L (1959) Neuropathological observations in phenylketonuria.Brain 82: 1–9.

    Google Scholar 

  • Schwab C, Brüchner G, Rothe T, Castellano C, Oliverio A (1992) Autoradiography of muscarinic cholinergic receptors in cortical and subcortical brain regions of C57BL/6 and DBA/2 mice.Neurochem Res 17: 1057–1062.

    Google Scholar 

  • Scholz W (1957) Contribution à l'anatomie pathologique du systeme nerveaux central dans l'oligophrenie phenylpyruvique.L'Encephale 46: 668.

    Google Scholar 

  • Shah SN, Peterson NA, McKean CM (1972) Lipid composition of human cerebral white matter and myelin in phenylketonuria.J Neurochem 19: 2369–2376.

    Google Scholar 

  • Sidman RL, Angevine JB, Taber-Pierce E (1971)Atlas of the Mouse Brain and Spinal Cord. Cambridge, MA: Harvard University Press.

    Google Scholar 

  • Takashima S, Chan F, Becker L (1991) Cortical dysgenesis in a variant of phenylketonuria (dihydropteridine reductase deficiency).Pediatr Pathol 11: 771–779.

    Google Scholar 

  • Taylor EH, Hommes FA (1983) Effect of experimental hyperphenylalaninemia on myelin metabolism at later stages of brain development.Int J Neurosci 20: 217–228.

    Google Scholar 

  • Thompson AJ, Smith I, Brenton D et al (1990) Neurological deterioration in young adults with phenylketonuria.Lancet 336: 602–605.

    Google Scholar 

  • Thompson AJ, Smith I, Kendall B, Yaul BD, Brenton D (1991) Magnetic resonance imaging changes in early treated patients with phenylketonuria.Lancet 337: 1224.

    Google Scholar 

  • Wall SJ, Yasuda RP, Li M, Ciesla W, Wolfe BB (1992a) The ontogeny of m1–m5 muscarinic subtypes in rat forebain.Brain Res Dev Brain Res 66: 181–185.

    Google Scholar 

  • Wall SJ, Yasuda RP, Li M, Ciesla W, Wolfe BB (1992b) Differential regulation of subtypes m1–m5 of muscarinic receptors in forebrain by chronic atropine administration.J Pharmacol Exp Ther 262: 584–588.

    Google Scholar 

  • Whitehouse PJ, Price DL, Strubble RG, Clarke AW, Coyle JT, DeLong MR (1982) Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain.Science 215: 1237–1239.

    Google Scholar 

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  1. F. A. Hommes

    Present address: Human Genetics Program, Department of Pediatrics, New York University Medical Center, 550 First Avenue, 10016, New York, NY, USA

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  1. Department of Biochemistry and Molecular Biology, Medical College of Georgia, 30912-2100, Augusta, GA, USA

    F. A. Hommes

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Hommes, F.A. The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH-5 mouse brain. J Inherit Metab Dis 16, 962–974 (1993). https://doi.org/10.1007/BF00711512

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  • DOI: https://doi.org/10.1007/BF00711512

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