Neurotrophic activity of pituitary adenylate cyclase-activating polypeptide on rat cerebellar cortex during development

High concentrations of pituitary adenylate cyclase-activating polypeptide ( PACAP) receptors are present in the external granule cell layer of the rat cerebellum during postnatal development. In vitro studies have shown that P ACAP promotes cell survival and neurite outgrowth on immature cerebellar gr anule cells in primary culture. In the present study, we have investigated the effect of PACAP on the development of the cerebellar cortex of 8-day-ol d rats. Incubation of cultured granule cells for 12 or 18 h with PACAP prov oked a significant increase in the rate of incorporation of [H-3]thymidine in cultured granule cells, suggesting that PACAP could stimulate the prolif eration of granule cells. After 96 h of treatment, in vivo administration o f PACAP provoked a transient increase in the number of granule cells in the molecular layer and in the internal granule cell layer. In contrast, PACAP did not affect the number of Purkinje cells, The augmentation of the numbe r of granule cells evoked by PACAP was significantly inhibited by the PACAP receptor antagonist PACAP(6-38). Administration of PACAP also caused a sig nificant increase in the volume of the cerebellar cortex. The present study provides evidence that PACAP can act in vivo as a trophic factor during ra t brain development, Our data indicate that PACAP increases proliferation a nd/or inhibits programmed cell death of granule cells, as well as stimulati ng neuronal migration from the external granule cell taper toward the inter nal granule cell layer.