Session 4: Neurotransmitters Systems in Autism
Diane C. Chugani, Ph.D.
Autism is a developmental disorder defined by the presence of a triad of communication, social and stereotypical behavioral characteristics with onset before 3 years of age. Underlying the spectrum of autistic behaviors are undoubtedly multiple etiologies, only a small fraction of which have been thus far identified. There is evidence for the potential involvement of several neurotransmitters in autism. We have applied alpha[C-11]methyl-tryptophan (AMT) as a PET tracer to estimate serotonin synthesis in autistic subjects. Gross asymmetries of AMT standard uptake value (SUV) in frontal cortex, thalamus and cerebellum were measured in a large number of children with autism. We also measured whole brain serotonin synthesis capacity in autistic and non-autistic children at different ages using AMT and PET. Global brain values for serotonin synthesis capacity were obtained for 30 healthy, seizure free autistic children, 8 of their healthy non-autistic siblings, and 16 epileptic children without autism. For non-autistic children, serotonin synthesis capacity was > 200% of adult values until the age of 5 years and then declined toward adult values. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1-1/2 times adult normal values. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children. Altered serotonergic neuromodulation of dentato-thalamo-cortical synaptic activity could be one pathophysiological mechanism underlying dysfunction in autism. We have also begun to investigate the brain distribution of GABAA receptor complex in children with autism, based on studies suggesting a role of GABAergic mechanisms in autism. Eleven autistic children (2 girls and 9 boys, mean age 9.9 years) underwent positron emission tomography (PET) using the tracer [C-11]flumazenil (FMZ), a ligand which binds the GABAA receptor. Statistical parametric mapping (SPM) was applied to define the pattern of FMZ binding in the patients compared to 8 age-matched children with temporal lobe epilepsy (3 girls and 5 boys, mean age 12.4 years) and 7 normal adult subjects (3 women and 4 men, mean age 37.5 years). The SPM analysis showed decreased FMZ binding in the autistic group bilaterally in the medial occipital cortex, bilaterally in temporal cortex and in right cerebellar cortex compared to epileptic children and adult controls, whereas decreased binding was only detected in the occipital cortex in the comparison of the autistic children with the children with epilepsy. We also measured the whole brain volume of distribution for GABAA receptors in the same subjects. In non-autistic subjects, global brain values for FMZ volume of distribution were highest in the youngest children and declined exponentially with age. FMZ volume of distribution values were significantly lower in 4 of the autistic children studied, whereas the remaining autistic children showed values which did not differ from the non-autistic group. I will discuss the significance of functional abnormalities measured in autistic children with PET in conjunction with data regarding the roles of these neurotransmitters during brain development from the animal literature.
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