Regional differences in the ontogeny of the serotonergic projection to the cerebral cortex.

We used light and electron microscope immunocytochemistry to compare the development of the pattern of innervation and synaptic organization of the serotonin (5-HT) afferent system in sensory (visual and somatosensory) and motor areas of the rat cerebral cortex. Serotonin-labeled fibers were present in all cortical areas at birth appearing as two tangential streams, one above and one below the cortical plate. These fibers gradually arborized sending branches into all cortical layers in an "inside-out" sequence that broadly paralleled the gradient of neurogenesis and differentiation in the cortex. A striking feature at the early stages of postnatal development of the visual and somatosensory cortex was the transient presence of a dense accumulation of 5-HT fibers in layer IV. In agreement with earlier reports, transient aggregations of serotonergic axons characterized sensory but not motor areas of the cortex. The innervation pattern characteristic of the adult cortex was attained by the end of the 3rd postnatal week. Electron microscopic analysis of the developing visual cortex showed that 5-HT-containing axonal varicosities formed synaptic contacts, predominantly of the asymmetrical variety, throughout postnatal life. The proportion of varicosities forming synapses increased gradually from birth to reach a peak at the end of the 2nd week, then declined markedly in the subsequent week before rising again at later stages. It appears that the formation of exuberant synapses by 5-HT axons coincides with the period of maturation of the neuronal circuitry of this cortical area. When quantitative analysis was restricted only to layer IV, the proportion of varicosities forming synapses reached a peak at the end of the 1st week of life, when transient innervation was most prominent in this layer. These results suggest that the effects of this dense band of serotonergic axons may be mediated through axodendritic synapses. The types of postsynaptic elements involved in the formation of synapses varied according to age, suggesting progressive morphological differentiation of cortical target neurons or, alternatively, a continuous process of removal and establishment of new connections by 5-HT axons in the visual cortex. In contrast, analysis in the motor cortex revealed a continuous increase in the proportion of 5-HT varicosities engaged in synaptic contacts from birth to the late sages of development. The results presented here provide anatomical evidence for a differential role of 5-HT in the maturation of the cerebral cortex.