0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

CAMPUS.1 – Analysis of developmental interactions between reelin haploinsufficiency, male…
significant role in non-motor cognitive processing, such as sociability, attention
shifting, language and explorative functions [Townsend et al. 2001; Brambilla
et al. 2003; Pierce, Courchesne 2001; Shu et al. 2005; Restuccia et al.
2007], that are impaired in autism. Furthermore, studies performed in patient
series from autistic populations confirmed the involvement of cerebellum.
Autistic brains constantly show a reduced number of Purkinje cells (PC), primarily
in the posterior inferior regions of the cerebellar hemispheres [Bauman,
Kemper 1985; Ritvo et al. 1986; Kemper, Bauman 1998; Bailey et al.
1998; Lee et al. 2002]. It is not known whether in autism PCs are generated
during development, correctly placed within the cerebellum and then later
lost, or whether they are never correctly placed or perhaps even never generated
during development.
There are several evidences for a neurotoxic effect of mercury (Hg). In
particular, such a phenomenon has first been described after mass intoxication
occurring in ’50s in Japan (Minamata) and in ’70s in Iraq [see the review
by Clarkson 2002]. Even though the massive exposure which occurred in
Japan and Iraq represented extraordinary situations, in modern era a constant
chronic exposure to Hg has been shown to occur worldwide [United
States Environmental Protection Agency 1997; Agency for Toxic Substances
and Disease Registry 1999]. Among compounds containing Hg, an important
source of human intake has been shown to be the oral one, and especially via
organo-mercurial compounds: among them the one which is considered as
the most commonly found in food is methyl mercury (MeHg) [see for instance
Mahaffey 1999; Clarkson 2002]. Thus, the toxic effects of this compound have
been repeatedly investigated in the last 20 years in a variety of experimental
settings involving mainly rats and mice.
The neurotoxic effects of Hg, including those produced by MeHg, significantly
involve the cerebellum, both at the level of granule cells and of PCs [see
for instance the review by Castoldi et al. 2001] and several mechanisms have
been proposed for such neurotoxicity so far [Castoldi et al. 2001]. Also of relevance
to the present project, exposure of adult rats to Hg phenylacetate has
been shown to induce alterations of dendritic spines in the parietal cortex
[Kozick, Grottel 1978] although at a much higher doses than the dose range
of the present project.
A variety of studies showed a significant lower threshold of the immature
brain to the toxic effects of MeHg, as compared with adult brain. The first
hints of such a phenomenon came from isolated reports of severe brain malformations
in offsprings of apparently healthy mothers from the Minamata
area. Afterwards, even the definition of a dose-response curve of mothers’ hair
Hg concentration (an index of chronic MeHg accumulation) and off springs
toxicity has been attempted [Marsch et al. 1987; Cox et al. 1989]. However,
despite several attempts to clearly establish a threshold level of MeHg exposure
in mothers for the occurrence of malformations in children, no unanimously
accepted levels have been determined so far, even though recently the
United States Environmental Protection Agency proposed 10 parts per million
(ppm) in maternal hair as a “ safe ” threshold level [see Clarkson 2002; United
States Environmental Protection Agency 2001].
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