(A) PDE4A5catnull expression in hippocampal neurons did not significantly affect PDE4 activity in the hippocampus (n = 7, Student’s t test p=0.097). (B) PDE4 activity in the prefrontal cortex was not altered by expression of the catalytically inactive PDE4A5catnull in the hippocampus (n = 7–8, Student’s t test p=0.162). (C) PDE4 activity in the cerebellum was not changed by expression of the catalytically inactive PDE4A5catnull in the hippocampus (n = 7–8, Student’s t test p=0.293). (D) Expression of the catalytically inactive PDE4A5catnull in hippocampal neurons did not alter the total time spent exploring objects during training in the object-place recognition task (n = 8–10, two-way ANOVA, effect of virus F1,33 = 0.043, p=0.873). All groups show a decrease in the total object exploration time during consecutive training sessions (two-way ANOVA effect of session F2,66 = 32.777, p=0.0001). Mice expressing PDE4A5catnull had a slightly but non-significantly lower object exploration time during the first training session, and a slightly but non-significantly higher object exploration time during the last training session (interaction effect F2,66 = 4.875, p=0.011, one way ANOVAs per session, p>0.05). (E) Mice expressing PDE4A5catnull spend a similar time in the periphery of the open field as mice expressing eGFP in hippocampal neurons (n = 8, Student’s t test, p=0.292). (F) Mice were injected with pAAV9-CaMKIIα0.4-eGFP or pAAV9-CaMKIIα0.4-PDE4A5catnullΔ4-VSV into the hippocampus to drive neuronal expression of eGFP or catalytically inactive full-length PDE4A5 which lacked the N-terminal domain unique for PDE4A5 (PDE4A5catnullΔ4). A VSV-tag was included to discriminate between endogenous PDE4A5 and the truncated PDE4A5catnullΔ4. (G) PDE4A5catnullΔ4 protein levels in the hippocampus 4 weeks after viral injection. A sample blot probed with an isoform-nonspecific PDE4A antibody revealed the presence of both wild-type PDE4A5 protein and truncated PDE4A5catnullΔ4 protein. Probing the blot with an antibody for the HA-tag confirmed that the truncated protein is indeed the N-terminal lacking catalytically inactive PDE4A5catnullΔ4. Each band represents an individual animal (H) Expression of the catalytically inactive PDE4A5catnullΔ4 lacking the N-terminal domain in hippocampal neurons did not affect total object exploration time during training in the object-place recognition task (n = 7–9, two-way ANOVA effect of virus F1,29 = 0.470, p=0.498). All groups show decreased total object exploration times during consecutive training sessions (two-way ANOVA effect of session F2,58 = 13.597, p=0.0001; interaction effect F2,58 = 0.555, p=0.557). (I) Mice expressing eGFP or the N-terminal domain lacking inactive form of PDE4A5catnullΔ4 were trained in the hippocampus-dependent object-place recognition task. Sleep deprivation causes memory deficits in both eGFP and PDE4A5catnullΔ4 mice (n = 7–9; two-way ANOVA effect of sleep deprivation F1,29 = 18.131, p=0.0001; effect of virus F1,29 = 1.064, p=0.311; interaction effect F1,29 = 0.001, p=0.986; eGFP NSD versus EGFP SD, posthoc Tukey’ t test p=0.0054; PDE4A5catnullΔ4 NSD versus PDE4A5catnullΔ4 SD, posthoc Tukey’ t test p=0.0037). Dotted line indicates chance level performance. NSD: non-sleep deprived, SD: sleep deprived. Values represent the mean ± SEM. #p<0.01 by Tukeys t test.