UC Santa Barbara

Serotonin (5-hydroxytryptamine, 5-HT) serves an important modulatory role in the entire central nervous system (CNS), and serotonergic abnormalities have been implicated in many mental disorders. All of the CNS supply of 5-HT originates in the brainstem raphe nuclei. The midbrain dorsal raphe nucleus (DRN) sends widespread projections to the forebrain but receives direct input from only a small number of forebrain regions, including the medial prefrontal cortex (mPFC). We hypothesized that prenatal perturbations of 5-HT levels may alter the forebrain expression of 5-HT receptors (5-HTRs) in a time-sensitive manner and that these changes may result in persistent changes of the forebrain control of the DRN. Specifically, this thesis investigated the susceptibility of 5-HTR expression in the embryonic mouse telencephalon to chronic and acute perturbations of 5-HT levels and examined the effects of altered 5-HT4R expression on the synaptic structure of the mPFC-DRN projection. These studies demonstrated (i) that acute and chronic perturbations of 5-HT levels affect the expression of 5-HT1AR, 5-HT2AR, and 5-HT4R in the embryonic forebrain and (ii) that altered 5-HT4R expression affects the development of the synaptic connectivity between mPFC terminals and DRN serotonergic neurons. These findings suggest that prenatal serotonergic perturbations can strongly influence the development of the prefrontal control of 5-HT signaling and have long-term consequences for behavioral responses later in life.