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During development of the rat cerebellum, PAC1receptors are transiently expressed by neuroblasts of the external granule cell layer (EGL). We have previously shown that PACAP is a potent stimulator of granule cell survival in vitro. In the study reported in this paper, we have investigated the effect of PACAP on the development of the rat cerebellar cortex in vivo. PACAP induces a transient increase in the volume of the cerebellar cortex, with a maximum effect at postnatal day 12, which can be accounted for by an increase in the number of granule cells in the EGL, the molecular layer, and the internal granule cell layer (IGL). The effect of PACAP on the number of granule cells is blocked by the antagonist PACAP(6-38), which, by itself, produces a slight inhibition of the number of granule cells in the IGL. These data indicate that PACAP activates proliferation andor inhibits programmed cell death of granule cells in the developing rat cerebellum. PACAP also stimulates neuronal migration from the EGL to the IGL. Thus, it appears that PACAP can act in vivoas a neurotrophic factor controlling histogenesis of the cerebellar cortex.

In vitrostudies have shown that PACAP promotes cell survival and neurite outgrowth in immature cerebellar granule cells. In the present study, we have examined the transduction pathways involved in the neurotrophic activity of PACAP. Incubation of cultured granule cells with graded concentrations of PACAP produced a dose-dependent increase in c-fosmRNA level. The effects of PACAP on c-fosgene expression and granule cell survival were both mimicked by dbcAMP but not by PMA. The maximum effect of PACAP on c-fosgene expression was observed after 1 h of treatment. Similar effects of the peptide on granule cell survival were observed whether the cells were continuously incubated with PACAP for 48 h or only exposed to PACAP during 1 h. The PKA inhibitor H89 significantly reduced the effect of PACAP on c-fosmRNA level, whereas the specific PKC inhibitor chelerytrine had no effect. These data indicate that the action of PACAP on cerebellar granule cell survival and c-fosgene expression are both mediated through the adenylyl cyclasePKA pathway.