engleski

Neurobiological basis of autism

Autism is a neurodevelopmental syndrome with onset in early childhood. The spectrum of symptoms varies among individuals, but includes some shared features: disturbances in social interactions, language and communication, and presence of stereotyped behaviors. Prevalence of autism in general population is 3-6 per 1000, but there is a high recurrence risk of 2-8 % in siblings of the diseased, and up to 92% in monozygotic twins, pointing to the strong genetic component of this disorder. According to the present state of knowledge, the cause of autism involves multiple genes, interacting with each other and with environmental factors to lead to the alterations in early brain development, affecting primarily frontal and temporal cortex, cerebellum and limbic regions. In the search for the genetic basis of autism association studies, linkage analyses, and studies on animal models have been employed. Candidate genes indicated through association studies belong to the three major categories: regulators of brain development, regulators of neurotransmission, and regulators of cellular growth and development. Linkage analyses have consistently indicated several candidate regions: 7q, 2q, 16p, 17q, 15q. Also, using brain lesions, early intoxications/infections, or targeted inactivation of genes, several animal models displaying some traits of autism have been developed. So far, through a combination of the mentioned approaches four major candidate genes have been suggested:  3 subunit of the GABAA receptor, serotonin (5HT) transporter, reelen and engrailed-2. Several lines of evidence indicate that the alterations in 5HT neurotransmitter system might represent one of the biological substrates of autism. 5HT plays an important role in neurogenesis by controlling growth and maturation of target regions and its own neurons, pharmacological manipulation of 5HT transmission influences autistic symptoms, functional studies have shown alterations in brain 5HT synthesis capacity, while elevated 5HT levels in blood have been consistently found in about 30% of the patients. It is assumed that the presence of high levels of 5HT in blood during fetal development, before the blood-brain barrier is formed, could inhibit development of 5HT neurons and lead to the anatomical and functional alterations of the brain, typical for autism. Still, the mechanisms that lead to hyperserotonemia, the relationship between high blood 5HT level and 5HT dysfunction in the central nervous system, and its effect on development of autism are not understood. With the current project we are trying to unravel the nature of the relationship between hyperserotonemia and autism and, thereby, contribute to the testing of the above-mentioned hypothesis.

autism; brain; candidate genes; serotonin

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