2 One approach to dissecting this disease process involves focusing on a well-defined clinical component of the illness. For example,

deficits in cognitive abilities are thought to be the core features of schizophrenia because they occur with high frequency in individuals with schizophrenia, are relatively stable over the course of the illness, are independent of the psychotic symptoms of the disorder, are present in a milder form in individuals at genetic risk who do not become clinically ill,3 and are the best predictor of long-term functional outcome.4 Of the domains of cognition affected Inhibitors,research,lifescience,medical in schizophrenia, disturbances in working memory, the ability to transiently maintain and manipulate a limited amount of since information in order to guide thought or behavior, are accompanied by altered ARQ197 Sigma activation of the dorsolateral prefrontal cortex Inhibitors,research,lifescience,medical (DLPFC, Figure 1 A, B). The altered activation

of the DLPFC under such conditions might be specific to the disease process of schizophrenia because these disturbances Inhibitors,research,lifescience,medical are present in medication-naïve individuals with schizophrenia, but not in subjects with other psychotic disorders or major depression.5,6 Figure 1 A) Photograph of an unstained coronal block, containing the prefrontal cortex, cut immediately anterior to the corpus callosum through the left hemisphere of a postmortem human brain. This block also includes the adjacent anterior cingulate gyrus (ACG) … This review examines alterations in components of excitatory Inhibitors,research,lifescience,medical and inhibitory neurotransmission in DLPFC circuitry that might contribute to the impairments in working memory in

schizophrenia. Each mediator is considered from the perspective of which alterations reflect the disease process and which might be neuroplastic responses of the affected circuits. Although additional studies are required, existing data suggests that many of the alterations described below are probably also present in other cortical regions that are dysfunctional in schizophrenia.7 Neuroplasticity of excitatory cortical connections in schizophrenia Inhibitors,research,lifescience,medical Excitatory connections in the DLPFC are altered in schizophrenia The disease process of schizophrenia appears to involve deficient glutamate -mediated excitatory neurotransmission through the N-methyl-D-aspartic acid (NMDA) receptor.8,9 NMDA receptor antagonists such as phencyclidine (PCP) Anacetrapib or ketamine increase both positive and negative symptoms in patients with schizophrenia, and the administration of subanesthetic doses of ketamine to healthy individuals produces thought disorder and other features similar to those seen in schizophrenia.10 In addition, systemic administration of NMDA receptor antagonists disrupts working memory in rats,11 and application of an NMDA receptor antagonist to the DLPFC impairs working memory performance in monkeys.