[11C](R)

Although still a matter of controversy, disrupted in schizophrenia protein 1 (DISC1) was suggested as a potential inhibitor of phosphodiesterase 4 (PDE4). We used Disc1 locus impairment (LI) mice to investigate the interaction between PDE4 and DISC 1 in vivo and in vitro. [11C](R)-Rolipram binding was measured by PET in LI (n？=？11) and C57BL/6 wild-type (WT, n？=？9) mice. [11C](R)-Rolipram total distribution volumes (VT) were calculated and corrected for plasma-free fraction (fP) measured in a separate group of LI (n？=？6) and WT (n？=？7) mice. PDE4 enzyme activity was measured using in vitro samples of cerebral cortices from groups of LI (n？=？4), heterozygote (n？=？4), and WT (n？=？4) mice. Disc1 LI mice showed a 41% increase in VT (18？±？6 vs. 13±4？mL/cm3, P？=？0.04) compared to WT mice. VT/fP showed a 73% significant increase (90？±？31 vs. 52？±？15？mL/cm3, P？=？0.004) in Disc1 LI compared to WT mice. PDE4 enzymatic activity assay confirmed in vivo findings showing significant group differences (p？<？0.0001). In conclusion, PDE4 activity was increased in the absence of critical DISC1 protein isoforms both in vivo and in vitro. Additionally, [11C](R)-Rolipram PET was sensitive enough to assess altered PDE4 activity caused by PDE4–DISC1 interaction