Normal development of the neocortex is critically dependent upon precise signals mediated by specific neuromodulatory systems, such as serotonin (5-HT). Abnormal 5-HT signaling produces a number of long-term anatomical and physiological consequences including alterations in synapse structure and density, and alterations of cortical circuit activity. Such 5-HT-induced effects are correlated with mental retardation and a number of behavioral disorders, including learning deficits, depression, schizophrenia, attentional disorders, and sleep disturbances. While the evidence for 5-HT in shaping normal cortical development is abundant, little is known about the specific components of the 5-HT signaling system that regulate normal neocortical is abundant, little is known about the specific components of the 5-HT signaling system that regulate normal neocortical development. The goal of the present proposal is to examine the role of specific 5-HT signaling components (receptors, transporters) on modulation of synaptogenesis and circuitry in the neocortex. Critical to understanding the role of 5-HT in neocortical development is a determination of the specific modulatory role on 5-HT on cortical circuits and the underlying mechanisms. The hypothesis to be tested is that 5-HT facilitates circuit activity later in development and in mature animals. The specific 5-HT receptors that mediate this developmental switch will be determined, with the hypothesis being that the facilitation is due to transient expression of specific 5-HT receptors in developing pyramidal neurons. 5-HT signaling is determined by the availability of 5-HT levels. However, how SERTs regulate synaptogenesis and circuit signaling during development is not known. The hypothesis to be tested is that SERT expression correlates with 5-HT levels in order to maintain appropriate extracellular 5-HT levels in cortex. Furthermore, it is hypothesized that disruption of SERT function will lead to changes in normal synaptogenesis and circuit signaling. These data will not only provide information regarding the role of specific 5-HT receptors and SERTs in cortical development, but will also be important in understanding the mechanisms underlying abnormal development of cortex related to inappropriate 5-HT signaling.
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