The Disrupted In Schizophrenia 1 (DISC1) gene was identified as a genetic risk factor for schizophrenia and affective disorders because it is disrupted by a balanced chromosomal translocation that co-segregates with major psychiatric illness (schizophrenia, bipolar affective disorder and severe recurrent depression) in a large family from Scotland (1). Several genetic studies have since provided further evidence for involvement of DISC1 in psychiatric illness, and in associated cognitive functions (1). DISC1 interacts with phosphodiesterase 4B (PDE4B), an independent risk factor identified due to disruption of the gene by a chromosomal translocation in cousins diagnosed with schizophrenia and psychosis (2). Subsequent genetic studies have confirmed the involvement of PDE4B in causing susceptibility to psychiatric illness, and intriguingly have also demonstrated a likely involvement of the related PDE4D gene (3). PDE4B and PDE4D are members of the four gene PDE4 family (PDE4A-D), and DISC1 can bind protein isoforms expressed from each gene (2). PDE4s are homologues of the drosophila Dunce gene involved in learning and memory (4). Cyclic AMP hydrolysis activity of PDE4 isoforms is inhibited by the prototypic antidepressant drug rolipram (4), and mice deficient in PDE4B and PDE4D behave as if on antidepressants (5). Thus the interaction between DISC1 and PDE4s is likely to be of direct relevance to the pathology of major mental illness. DISC1 binding to PDE4s is cAMP-dependent, with specific isoforms dissociating in response to elevated cAMP levels, conditions which also lead to PDE4 activation (2). It is therefore possible that DISC1 sequesters PDE4 in an inactive state, releasing active PDE4 when cAMP signalling cascades are switched on, and thus modulating cAMP signalling. Two ENU-induced Disc1 missense mutations have been identified in mice, leading to phenotypes related to schizophrenia and depression that respond to antipsychotic and antidepressant (including rolipram) drug treatment. These mutations are located within PDE4B contact sites and result in significantly reduced binding between Disc1 and PDE4B isoforms. One mutation is also associated with significantly reduced PDE4B catalytic activity. Altered Disc1/PDE4B function is therefore critical to the phenotypes of these mice, suggesting that the same may be true of human psychiatric disorders.