Disrupted-in-Schizophrenia-1 (DISC1) is a risk factor for major mental illness, including schizophrenia and depression. 1 DISC1 interacts with multiple proteins involved in intracellular signalling pathways, including two enzymes cAMP phosphodiesterase-4 (PDE4) 2 and glycogen synthase kinase-3β (GSK3β), 3 that are inhibited by the prototypic antidepressant/antipsychotic Rolipram4 and the mood stabiliser Lithium (LiCl), 5 respectively. PDE4 itself has been directly implicated as a risk factor for mental illness, 1, 2, 6 whereas the likely involvement of GSK3β in molecular pathways underlying mental illness is long standing and now linked to DISC1. 7 DISC1 inhibits GSK3β, 3 and we have previously suggested that DISC1 similarly modulates PDE4. 2 These enzymes have overlapping binding sites on DISC1, 3, 8 suggesting that their function within the DISC1 complex may be related. Moreover, it has recently been demonstrated that GSK3β phosphorylates PDE4D. 9 Accordingly, we now provide evidence that pharmacological inhibition of GSK3β decreases PDE4 activity, and demonstrate that the stimulatory effect of Forskolin upon PDE4 activity is modulated by the co-ordinated action of DISC1 and GSK3β. Treatment of the human neuroblastoma cell line SH-SY5Y with 10mM LiCl, a non-selective inhibitor of GSK3β, results in increased cAMP accumulation (Figure 1a, P= 0.000006), suggesting that GSK3β modulates cellular cAMP levels. We therefore performed phosphodiesterase activity assays on SH-SY5Y cells to determine if LiCl effects on cAMP levels involved PDE4. At basal cAMP levels, a trend towards PDE4 inhibition was observed after treatment with 3mM LiCl, and significantly decreased PDE4 activity was observed at 10 mM LiCl (Figure 1b, P= 0.000001), suggesting that GSK3β has a tonic-activating effect on PDE4. A decrease in PDE4 activity was also observed