There is accumulating evidence that AKT signaling plays a role in the pathogenesis of schizophrenia. We asked whether Akt1 deficiency in mice results in structural and functional abnormalities in prefrontal cortex (PFC). Exploratory transcriptional profiling revealed concerted alterations in the expression of PFC genes controlling synaptic function, neuronal development, myelination, and actin polymerization, and follow-up ultrastructural analysis identified consistent changes in the dendritic architecture of pyramidal neurons. Behavioral analysis indicated that Akt1-mutant mice have normal acquisition of a PFC-dependent cognitive task but abnormal working memory retention under neurochemical challenge of three distinct neurotransmitter systems. Thus, Akt1 deficiency creates a context permissive for gene-gene and geneenvironment interactions that modulate PFC functioning and contribute to the disease risk associated with this locus, the severity of the clinical syndrome, or both. mouse model ͉ psychiatric disease ͉ susceptibility gene T here is accumulating evidence that AKT signaling plays a role in the pathogenesis of schizophrenia. This includes convergent evidence for a decrease in Akt1 protein levels and levels of substrate phosphorylation in brains of some individuals with schizophrenia (1, 2), a greater sensitivity to the sensorimotor gating-disruptive effect of amphetamine in an Akt1-deficient mouse model (1), as well as pharmacological evidence indicating that drugs used in the management of psychosis such as lithium, haloperidol and clozapine, can act as enhancers of AKT signaling in vivo (1, 3), or in vitro (4). Indeed, AKT is a key signaling intermediate downstream of dopamine receptor D2 (DRD2), the best-established target of antipsychotic drugs. AKT function is important for normal dopaminergic transmission and expression of dopamine-associated behaviors (5) in a manner distinct from, but perhaps cooperative to, cAMP͞DARPP32-dependent signaling, traditionally associated with the D1 class of receptors. An association between schizophrenia and AKT1 genetic variants has also been reported in three large family samples of European descent (1, 6, 7), but not in a family sample of Asian descent (8).A diverse and convergent body of data from both in vivo and postmortem approaches suggests that prefrontal cortex (PFC) is central to the pathophysiology of schizophrenia (9-14). Although studies of individuals with schizophrenia are, in principle, confounded by the effect of treatment and the course of the disease, more recent studies of animal models of leading candidate susceptibility genes (15, 16) that are free of such confounding influences, also reveal deficits in PFC functioning. Individuals with schizophrenia show varying degrees of deficiency in a diverse range of cognitive domains (17). In particular, deficits that are attributed primarily to PFC dysfunction, such as impaired working memory (18), are considered a cardinal cognitive symptom of schizophrenia (19). Previous work in animal models has sh...