Relationship between myelin production and dopamine synthesis in the PKU mouse brain
Article first published online: 3 JUL 2003
Journal of Neurochemistry
Volume 86, Issue 3, pages 615–626, August 2003
How to Cite
Joseph, B. and Dyer, C. A. (2003), Relationship between myelin production and dopamine synthesis in the PKU mouse brain. Journal of Neurochemistry, 86: 615–626. doi: 10.1046/j.1471-4159.2003.01887.x
- Issue published online: 3 JUL 2003
- Article first published online: 3 JUL 2003
- Received March 11, 2003; revised manuscript received April 22, 2003; accepted April 24, 2003.
- blood–brain barrier;
Phenylketonuria is caused by specific mutations in the phenylalanine hydroxylase gene and is characterized by elevated blood phenylalanine levels, hypomyelination in forebrain structures, reduced dopamine levels, and cognitive difficulties. To determine whether brain tyrosine levels and/or myelination play a role in the up-regulation of dopamine, phenylketonuric mice were placed on a low phenylalanine diet for 4 weeks and as blood phenylalanine levels dropped to normal, the relationships between phenylalanine, tyrosine, dopamine, myelin proteins, and axonal proteins in frontal cortex and striatum were determined using gas chromatography mass spectrometry, histology, and western blotting techniques. Blood phenylalanine rapidly decreased from an eight-fold elevation to near control levels, and blood tyrosine gradually rose from about 50% to near normal values. In frontal cortex and striatum, phenylalanine levels dropped to 2- and 1.5-fold elevations above control, respectively, and tyrosine levels increased but remained less than 70% of control in both structures. In frontal cortex, increases in dopamine and myelin basic protein occurred in a similar biphasic pattern, reaching near normal levels by week 4. In striatum, dopamine and MBP dramatically increased to near normal levels in the first week. Myelination was confirmed histologically and by western blot quantification of phosphorylated neurofilaments. In summary, our results showed: (i) an increase in dopamine despite low brain tyrosine levels and (ii) similar recovery patterns for myelination and dopamine. Since myelin/axonal interactions trigger signaling pathways that result in axonal maturation, we speculate that this interaction also may trigger signals that up-regulate neurotransmitter synthesis.