Adult early treated hyperphenylalaninaemic patients can show specific deficits of prefrontal cortical functions. The development of additional therapeutic strategies for these patients requires the understanding of the mechanisms involved in phenylalanine-dependent impairment of fronto-cortical functions. We tested the hypothesis of phenylalanine interference with aminergic neurotransmission in the prefrontal cortex by evaluating, in vivo, amine release in adult Pah(enu2) mice, the genetic model of phenylketonuria. Mice of healthy background responded to a psychogenic stressor with the classic time-dependent increase of norepinephrine, dopamine and serotonin release from prefrontal cortical terminals. Neither the dopaminergic nor the serotoninergic responses were observable in the Pah(enu2) mice. Temporary reduction of circulating phenylalanine, by phenylalanine-free diet without amino- acid supplement, promoted recovery of the serotonin response only, demonstrating direct interference with serotonin synthesis in the mature brain. Evaluation of different steps of serotonin synthesis in the prefrontal cortex of hyperphenylalaninaemic mice demonstrated inhibition of cortical tryptophan hydroxylase activity. Finally, systemic administration of 5-hydroxytryptophan, the product of tryptophan hydroxylase activity, allowed frontal cortical serotonin response to stress in hyperphenylalaninaemic mice. Collectively, these results demonstrate that hyperphenylalaninaemia interferes with the ability of the mature prefrontal cortex to respond to psychological challenges, point to serotonin synthesis as the target of phenylalanine interference, and support the use of 5-hydroxytryptophan in lifelong treatment of hyperphenylalaninaemic subjects.
These findings indicate that ST phenotype can be the expression of a transitory late developmental stage and that genetic factors determine persistence of this phenotype in adulthood. These findings also support a role of 5-HT transmission in PFC in constraining development of ST phenotype.
This short review presents the hypothesis that stress-dependent dopamine (DA) transmission contributes to developing and maintaining the brain network supporting a cognitive reserve. Research has shown that people with a greater cognitive reserve are better able to avoid symptoms of degenerative brain changes. The paper will review evidence that: (1) successful adaptation to stressors involves development and stabilization of effective but flexible coping strategies; (2) this process requires dynamic reorganization of functional networks in the adult brain; (3) DA transmission is amongst the principal mediators of this process; (4) age- and disease-dependent cognitive impairment is associated with dysfunctional connectivity both between and within these same networks as well as with reduced DA transmission.
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