Effects of neonatal serotonin depletion on the development of rat dentate granule cells.

The appearance of serotonergic (5-HT) neurons and projections early in central nervous system (CNS) development has resulted in the hypothesis that 5-HT is an important factor in neuronal differentiation and synaptogenesis. Studies of the effects of 5-HT on the development of molluscan and mammalian neurons in vitro support this hypothesis, but mammalian in vivo studies have produced equivocal results. The present study reinvestigated the role of 5-HT in CNS development using the dentate granule cell as a model. Dentate granule cells were chosen for this study of the effects of 5-HT depletion on neuronal development because they are generated in the early postnatal period. Thus, 5-HT depletion could be effected by the treatment of rat pups with either parachloroamphetamine (PCA) or 5,7-dihydroxytryptamine (5,7-DHT) thereby avoiding problems inherent in maternal treatment paradigms. The morphology of Neurobiotin-filled granule cells was studied on P14, P21, P60 and P120 (P0 = day of birth). The parameters measured were total dendritic length, number of dendritic segments and dendritic spine density (number of spines/50 microns dendritic length). Granule cells from vehicle-treated controls were similar to those previously reported in studies of normal granule cell development in all respects. In particular, the decrease in dendritic spine density from P14 to P120 observed in Golgi preparations was verified in our population of intracellularly filled granule cells. Transient depletion of 5-HT by neonatal PCA treatment resulted in a decrease dendritic length that was not statistically different from control values. However, dendritic spine density was reduced by about 27% at all ages studied. 5,7-DHT treatment produces a permanent, severe depletion of 5-HT. Spine densities in granule cells from 5,7-DHT-treated pups were also about 38% lower than controls. Total dendritic length in cells from 5,7-DHT-treated rats was reduced to a degree comparable to that observed in PCA-treated pups. The number of granule cell dendritic segments was also less than that observed in control and PCA-treated rats but this difference was not statistically significant. These observations suggest that reduction of 5-HT in the early postnatal period can result in changes in the morphology of dentate granule cells, particularly at the level of the synapse as reflected by the permanent reduction in synaptic spine density. The comparison of results from cases with permanent and transient reduction of 5-HT indicates that the developmental influence of 5-HT is most important during the first three postnatal weeks.