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Impact of autism-related peptides and 5-HT system manipulations on cortical development and plasticity

Objective

To isolate peptides from the urine of autistic children that affect human serotonin transporter function.

To test the effect of these peptides on the differentiation of synaptic connections in the cerebral cortex of newborn rats.

To investigate the role of serotoninergic transmission in the postnatal development and plasticity of the cerebral cortex.

Infantile Autism is a severely invalidating syndrome of unknown origin, 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 investigate the pathogenesis of autistic symptoms. Recent findings show that a large subset of autistic children have abnormally high levels of casein- and gluten-derived peptides in their body fluids ("autism-related peptides", ARPs). We will collaboratively assess the impact of purified ARPs on development and plasticity of brain circuits in the rat somatosensory cortex, using a variety of histochemical, immunohistochemical, electron-microscopic, and tracing techniques. Preliminary evidence shows that ARPs may selectively enhance 5-HT transporter function in platelets. Interestingly, increased platelet 5-HT content represents the most consistent alteration in monoaminergic turnover found in autistic patients. Enhanced brain 5-HT transport might lead to decreased 5-HT levels in the synaptic cleft, possibly associated with impulsive and aggressive behaviors, attention deficits, sleeplessness, and hyperalgesia. Furthermore, 5-HT may be required for the fine-tuning of synaptic connections in the mammalian central nervous system after birth. In our collaborative effort, we shall first assess the effect of ARPs on the human 5-HT transport system expressed in vitro, and then in the developing rat brain. Furthermore, the 5-HT system in the rat brain will be manipulated by pharmacological agents, and by generation of a transgenic mouse with 5-HT transporter knock-out. Evidence supporting ARP-induced derangement of development and plasticity in the cortex would be strongly suggestive of their involvement in the pathogenesis of autistic symptoms, and would spur our interest in the development of screening methods for ARPs, aimed at detecting their presence before neural connectivity is definitively established. Finally, positive results would pave the way for early pharmacologic intervention in children with abnormally high levels of autism-related peptides.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

Libero Istituto Universitario Campus Bio-Medico
Address
Via Longoni 83
00155 Roma
Italy

Participants (4)

Bayerische Julius-Maximilians-Universität Würzburg
Germany
Address
2,Sanderring
97070 Wuerzburg
Istituto di Ricerche di Biologia Molecolare P. Angeletti SpA
Italy
Address
Via Pontina Km 30.6
00040 Pomezia Roma
Rijkshospitalet Oslo
Norway
Address
Km.30,rijkshospitalet
0027 Oslo
Universidad de Navarra
Spain
Address
15,University Of Navarra
31038 Pamplona