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Ricerca>Progetti>Biomed
2
| Full title | Impact of autism-related
peptides and 5-HT system manipulations on cortical development and plasticity |
Summary
| Infantile Autism
is a severely invalidating syndrome which affects 5/10.000 newborn children, yielding
a European autistic population of approximately 200.000 individuals. The disorder
is characterized by early onset, poor or no attention to the outside world, lack
of speech, stereotyped behavior, sleeplessness, and self-injurious conduct. No
effective cure is presently known. The primary goal of our research project is
to tackle basic questions related to the pathogenesis of autistic symptoms, with
the aim of developing a screening test, and of setting up strategies for early
therapeutic intervention. The project is based on recent findings, showing that
a large subset of autistic children have abnormally high levels of casein- and
gluten-derived peptides in their body fluids ("autism-related peptides").
Following initial purification of autism-related peptides from the urine of autistic
patients, we will collaboratively assess their impact on development and plasticity
of brain circuits. In particular, we shall analyze autism-related peptide effects
on neural structures and connections in the rodent somatosensory "barrel"
cortex, the best-studied rodent model for cortical development and plasticity,
using a variety of standard histochemical, immunohistochemical, electron-microscopic,
and tracing techniques. In reference to potentialmechanisms of action of autism-related
peptides, preliminary results indicate that some of these molecules may selectively
enhance 5-HT transporter function in platelets. Similarly, enhanced 5-HT transport
in the brain might lead to decreased 5-HT levels in the synaptic cleft, possibly
associated with impulsive and aggressive behaviors, attention deficits, sleeplessness,
and hyperalgesia. Interestingly, increased platelet 5-HT content represents the
most consistent alteration in monoaminergic turnover found in autistic patients.
Little is currently known about the potentially pivotal role of 5-HT in the fine-tuning
of synaptic connections occurring in the mammalian central nervous system after
birth. Such pivotal role is strongly suggested by classical studies on invertebrates
including Aplysia In our collaborative effort, we shall first replicate experiments
performed on platelets, using a eukariotic cell system, selectively expressing
the human 5-HT transporter. A series of experiments will then be performed in
the developing rodent brain, following manipulations of the 5-HT system by pharmacological
agents, or by generation of transgenic mice with a knock-out of the 5-HT transporter
or of the 5-HT,A receptor. Evidence supporting autism-related peptide-induced
derangement of development and plasticity of cortical connections, possibly mediated
by the 5-HT system, would be strongly suggestive of their involvement in the pathogenesis
of autistic symptoms, and would spur our interest in the development of screening
methods, aimed at an early diagnosis, possibly occurring before neural connectivity
is definitely established. Finally, these results would underscore the need for
early therapeutic interventions in children with abnormally high levels of autism-related
peptides potentially involving also pharmacologic strategies modulating the 5-HT
system. | | Time frame | Start
Date : 01-Jul-1996
End Date : 30-Jun-1999 | | Funded
by | European Commission | | Results | Final
public report | | Project leader
for Campus Bio-Medico | Flavio
Keller | | Main partners | Universidad
Autónoma de Madrid (ES), Rijkshospitalet Oslo (NO), Bayerische Julius-Maximilians-Universität
Würzburg (DE), Istituto di Ricerche di Biologia Molecolare "P. Angeletti"
SpA (IT) | | Campus Bio-Medico role | Main
contractor | | Reference web site | |
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