The induction of cyclic nucleotide phosphodiesterase 4 gene (PDE4D) impairs memory in a water maze task

In this study, the effects on memory of intraperitoneal post-training administration of cyclic nucleotide phosphodiesterase (PDE) inhibitors, DC-TA 46 and rolipram, were tested using a visible/hidden platform water maze task. The effects of these compounds on cyclic nucleotide levels in the hippocampus (HF) and striatum (CP) were also assessed, by EIA (enzymatic immuno assay). The results obtained from rats trained in the visible-platform task were not significantly different from controls. On the contrary, the animals trained in the hidden-platform water maze task showed a memory impairment, when injected with DC-TA 46 at maximal dose of 20 mg/kg and with rolipram at 3 mg/kg and 30 mg/kg doses. The effects of these drugs on cyclic nucleotide levels in HF and CP were observed at 30 minutes and at 24 hours after drug administration. Thirty minutes after drug injection we observed an increase of cAMP level, both in HF and in CP. Twenty four hours after the retention test, we observed that in CP the cAMP intracellular level remained high, while in the HF at effective doses both inhibitors induced cAMP PDE activity, determining a decrease of cyclic nucleotide. Semi-quantitative RT-PCR analysis, together with western blot immunodetection, showed a mRNA and protein induction of PDE4D phosphodiesterase isoforms, that may account for the increase of PDE activity observed. Our data suggest that, despite cyclic nucleotide increase at 30 minutes, the fundamental event causing memory impairment, came from the subsequent long time decrease of cAMP levels, due to the post-translational PDE4D induction.