0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
author [Roman 2007], in light of all the experimental data concerning a
pivotal role of thyroid hormones in neuronal maturation/differentiation.
Fetuses totally depend from mothers’ thyroid hormones circulating levels
up to mid gestation, and mercury significantly reduces circulating thyroid
hormones both in immature and adult mice. Since Reelin expression during
brain development has been shown to be strongly affected by thyroid
hormone levels [Alvarez-Dolado et al. 1999], Roman [2007] hypothesized
that mercury exposure might reduce Reelin expression through an early
reduction of thyroid hormones in critical brain developmental stages; furthermore,
specific Reelin gene polymorphism in selected autistic pedigrees
might amplify such a suppressive effect of mercury on thyroid hormones
[Roman 2007].
Even though in the present study we will not specifically explore the
effect of mercury exposure on thyroid hormones in reeler mice, the abovementioned
data give strength to such an hypothesis. The role of thyroid hormones
in the effect we will find might be the subject of future studies in our model.
PRELIMINARY DATA
In the last three years the PI and his colleagues have been intensively
involved in a study exploring the anatomical and behavioral phenotype of
male rl/+ mice, and the effects of modulating androgen and estrogen levels in
the cerebellum. The rl/+ mouse is particularly is interesting in view of the
reported decrease of Reelin expression in a subset of autistic patients [Fatemi
et al. 2002; 2005].
Using stereological analysis we have assessed total PC numbers in the
cerebella of wt, rl/+ and reeler (rl/rl) male and female mice during early postnatal
development. PC numbers are reduced in rl/+ males at postnatal day 15,
with no parallel loss of granule cells or inferior olivary neurons. Early postnatal
administration of the estrogen receptor (ER) agonist 17b-Estradiol in the
cisterna magna increases PC numbers in male rl/+ but has no effect in female
rl/+ or male/female wt mice; conversely, administration of the ER antagonists
4-OH-Tamoxifen or ICI 182,780 selectively reduce PC numbers in female wt
and rl/+, but has no effect in male rl/+ or wt mice. We hypothesize that PC loss
in the male rl/+ may be due to an imbalance of testosterone metabolism, since
at P5, compared to wt males, rl/+ male cerebella show increased levels of
testosterone and 17b-Estradiol, associated with decreased levels of dihydrotestosterone.
Decreased Reelin function and hormone imbalance may thus
interact during neurodevelopment to influence PC survival. Our results thus
support male rl/+ mouse as a model of developmental interaction between
genetic vulnerability and sex hormone levels on PC, which could be relevant
for neurodevelopmental disorders of genetic origin that are characterized by
increased male prevalence and cerebellar neuropathology, such as autism
spectrum disorders. These results are reported in detail in a submitted manuscript
[Biamonte et al. 2008, see attachment].
Behavioral analysis showed that basal levels of ultrasonic vocalizations in
rl/+ females were significantly lower than in wt. Administration of estradiol at
584 2009