0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
SPECIFIC AIMS
We propose here an in depth analysis of the interaction of an environmental
toxic agent, methylmercury (MeHg), genetic background and hormonal/sex
setting in determining the anatomical and behavioural phenotype in reeler heterozygous
mice (rl/+), haploinsufficient for Reelin. This mouse model can be
considered as an interesting model for autism in light of the following evidences
(a significant part of which have been produced by the proposing PI
and collaborators): a) Reelin is affected in several autistic pedigrees; b) rl/+
mice show a sex/gender related brain pathology, since only in males a selective
alteration of Purkinje cell layer in the cerebellum can be observed: similarly in
humans autism affect males 4 times more frequently than females; c) the cerebellum
is constantly involved in autistic brains, similarly to what observed in
our mouse model; d) recent evidence suggests that rl/+ mice display behavioral
deficits such as altered ultrasonic vocalizations upon separation from the
mother, and difficulties in changing behavioral strategies in adult life.
In particular we want to assess:
1) Whether chronic exposure to MeHg at a dose which is sub-toxic in
other strains of mice reproduces pathological changes resembling those found
in autistic brain, in wild type mice from our strain.
2) Whether such effects are different from those occurring in rl/+ mice.
3) Whether such effects are gender-dependent. In particular, do they
involve more frequently males, as expected to be the case in an optimal model
of autism?
4) In the case we reproduce a gender-dependent effect in which males are
more prone to be affected by MeHg than females: which is the effect of an
early manipulation of the hormonal milieu on such effects? In particular,
which are the effects of the elimination of the early postnatal testosterone
surge occurring in male mice on the outcome of Hg exposure?
5) Which are the molecular pathways on which environment, hormonal
internal milieu, and Reelin haploinsufficiency converge?
BACKGROUND AND RATIONALE
Autism is a disorder characterized by impaired social skills, repetitive and
stereotypic behaviors, impairments in planning and attention, deficits in sensorimotor
exploration and altered cognitive functioning [Rapin 2002; Rubenstein,
Merzenich 2003]. Twin studies support a strong genetic component
[Bailey et al. 1995]. Males are affected more frequently than females by a ratio
of 4:1.
Some authors have even proposed the theory of the “ autistic brain ” as an
extreme form of “ male brain ” [Baron-Cohen 2002], partly based on the
hypothesis that high prenatal testosterone levels may be a risk factor for
autism [Manning et al. 2001; Knickmeyer et al. 2006]. Among the brain
regions implicated, the cerebellum has become a critical point of investigation
based on functional and structural neuroimaging studies. Cerebellum plays a
580 2009