0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
SPECIFIC AIMS
1) To investigate the effects of 5-hydroxytryptophan (5-HTP) treatment
during critical postnatal period in phenylketonuric mice. This treatment will
be performed as alternative to standard low-PHE diet, and long-term effects
on behaviours of adult phenylketonuric mice will be evaluated.
2) To investigate the effects of 5-HTP treatment in adult mice characterized
by different forms of hypeprhenylalaninemia (HPA). Different forms of
HPA (control, mild HPA, mild phenylketonuria (PKU) and classic PKU) will
be modelled on the base of plasma phenylalanine concentrations, and the
effects of 5-HTP on frontal cognitive functions will be evaluated.
RATIONALE
1. What happen if you restore in ENU2 mice normal brain 5-HT levels
during critical period? Our first specific objective is to investigate effects of 5-
HTP during critical postnatal period to prevent cognitive dysfunctions in
phenylketonuric subjects.
Biogenic amines, in addition to their well-known function as neurotransmitters,
have important roles in brain development [Herlenius, Lagercrantz
2001]. The brain availability of biogenic amines follow a typical ‘phasic’ evolution
characterized by dramatic increases during specific age-windows followed
by reduction to adult levels. It has been suggested that neurotransmitter
overproduction favours brain maturation in critical periods, i.e. in developmental
stages during which condensing biochemical mechanisms are
required for brain growth events. Moreover, several studies showed that, in
developing animals, biogenic amines are implicated in the formation and
maintenance of synapses [Okado et al. 2001; Whitaker-Azmitia 2001].
In a previous study we identified age-dependent (postnatal days; 14-21)
deficits in brain amine availability during postnatal development in PAH enu2
(ENU2) mice, the genetic model of PKU [Pascucci et al. 2008]. In particular, 5-
HT deficits were most pronounced, indicating severe widespread reduction of
5-HT levels at all ages investigated, particularly between P14-P21, in comparison
with wild-type. The time window of brain amine availability identified by
this study in wild-type mice overlaps with the critical period of synapse formation,
dendritic growth and remodelling, axonal refinement and columnarization
in rodent’s cortices. Serotonin was the first neurotransmitter for which a
developmental role was demonstrated [Sodhi, Sanders-Bush 2004; Whitaker-
Azmitia 2001], and growing evidence implicates 5-HT in regulating the refinement
of synaptic connectivity during postnatal development [Mazer et al.
1997]. Deficits in 5-HT availability during critical maturation periods could
represent a major source of the pathologic alteration of axons, dendrites and
synapses remarked in the brain of untreated PKU patients [Bauman et al.
1982; Huttenlocher 2000; Kornguth al. 1992]. In agreement with these results,
unpublished data (see preliminary results, point 1) showed structural alterations
in pFC neurons in ENU2 mice. These alterations might be morphological
substrate of behavioural deficits reported in ENU2 mice [Cabib et al. 2003].
786 2009