The serotonergic (5-HT) neurotransmitter system plays a major role in modulating postnatal development of the brain, including neuronal differentiation, synaptogenesis and developmental plasticity. Perturbations in 5-HT neurotransmission affect neuronal development and plasticity. Studies in rodents and humans indicate that markers for serotonin neurotransmission are enhanced in the immature brain compared to adults. However PET studies show that the early rise in serotonin metabolism is blunted in some children with autism. Clinical trials with drugs targeting serotonin neurotransmission demonstrate ameliorative potential for several debilitating autistic deficits, e.g., self-injury; stereotypy; mood disorders; cognitive parameters. Proposed experiments will determine in an animal model that involves neonatal 5-HT depletions whether selected structural and pharmacological changes in neocortex resemble those observed in autistic patients. Consistent with recent findings of increases in cortical volume in autistic brains, we have recently shown that cortical width expands when 5-HT afferents to rodent cortex are depleted at birth with the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). As in autism, specific changes vary by sex, cortical region and hemisphere. These neonatal 5-HT depletions also precipitate behavioral changes, indicative of altered attentional processes. This has lead us to the hypotheses that the cerebral cortical alterations observed in autism, are 1) the result of altered development of the 5-HT innervation cortex and 2) that cognitive changes and disturbances in sensory processing are the consequence of altered cortical development.
Our specific aims are 1) to determine the time course of altered 5-HT innervation and function after neonatal 5,7 DHT injections into the medial forebrain bundle and 2) to characterize the effect of neonatal 5-HT depletion on development of thalamocortical connectivity and receptor ontogeny, 3) to characterize changes in social, affective and cognitive behaviors in mice with neonatal serotonergic depletions and to compare these to behavioral changes in mice with early prenatal serotonergic hypoinnervation and 4) to determine whether cortical volume is altered after neonatal 5-HT depletion and whether any alterations are due to changes in white or gray matter.
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