Abstract
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. [(11)C](R)-Rolipram binding was measured by PET in LI (n = 11) and C57BL/6 wild-type (WT, n = 9) mice. [(11)C](R)-Rolipram total distribution volumes (V(T)) were calculated and corrected for plasma-free fraction (f(P)) 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 V(T) (18 ± 6 vs. 13±4 mL/cm(3), P = 0.04) compared to WT mice. V(T)/f(P) showed a 73% significant increase (90 ± 31 vs. 52 ± 15 mL/cm(3), 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, [(11)C](R)-Rolipram PET was sensitive enough to assess altered PDE4 activity caused by PDE4-DISC1 interaction.