Development of rolipram-sensitive, cyclic AMP phosphodiesterase (PDE4) in rat primary neuronal cultures.

The development of PDE4 was examined in primary neuronal cultures of rat cerebral cortex. Three days after culturing, neurons exhibited relatively low PDE4 activity (i.e., rolipram-sensitive PDE activity). It gradually increased over time, approximately doubling by day 12. The increase in activity was accompanied by an increase in the expression of the PDE4A variants, PDE4A5 and PDE4A1, as well as of the synaptic marker protein synapsin I. There was a strong correlation between the expression of the PDE4A variants with that of synapsin I, which suggests that as neurons develop and signal transduction increases there is a regulated increase in PDE4 expression and activity. Consistent with this interpretation, it was found that treatment with the sodium channel blocker tetrodotoxin, which inhibits depolarization-induced neurotransmitter release, reduced the expression of the PDE4A variants. These data demonstrate the developmental regulation of PDE4 in neurons and offer a manner by which the association of PDE4 variants with particular signal transduction pathways may be studied in vitro.