Under this scenario, the alterations of DLPFC circuitry in schizophrenia may render it unable to support higher levels of working memory load, rendering the impaired performance in schizophrenia analogous to the immature levels of working memory function seen
in children.93,94 Neuroplastic responses as targets for treatment The findings reviewed Inhibitors,research,lifescience,medical above indicate that working memory and related cognitive impairments in schizophrenia are likely the result of a complex set of alterations in GDC0449 prefrontal excitatory and inhibitory circuitry. Some of these alterations appear to be deleterious causes or consequences of disturbances in the functional architecture of the DLPFC and Inhibitors,research,lifescience,medical interconnected brain regions, whereas others may be best explained as compensatory responses. In each case, they reflect the morphological and molecular neuroplasticity of DLPFC circuitry in a disease state. Understanding whether the disease-related change in a given molecule is a consequence or compensation in the disease process has Inhibitors,research,lifescience,medical important implications both for the nature of activity of the drugs designed against that target and for the potential therapeutic value of the target. For example, is the neuroplastic capacity of cortical
circuitry sufficiently limited that pharmacological augmentation of a compensatory response is feasible? The results of a recent proofof -concept clinical trial suggest that this may be the case. For example, the idea that GABAA receptors α2 subunits are upregulated in pyramidal neurons due to
Inhibitors,research,lifescience,medical a deficit in GABA input from chandelier neurons led to the use of a novel, positive allosteric modulator of this receptor subtype that improved both working memory Inhibitors,research,lifescience,medical function and prefrontal gamma band oscillations in a small randomized controlled trial of subjects with schizophrenia.95 Given the marked developmental changes that occur in each of these systems during adolescence, this type of pharmacological intervention may have particular value as a treatment strategy for high-risk adolescents in the prodromal phase of the illness. However, the effectiveness and safety of such interventions requires a fuller understanding of the maturation of these neural circuits, of the functional consequences of these circuitry changes and of the vulnerability of these developmental processes from to pharmacological agents. Acknowledgments Cited work conducted by the author was supported by NIH grants MH045156, MH051234 and MH043784. Selected abbreviations and acronyms CCK cholecystokinin DLPFC dorsolateral prefrontal cortex GABA γ-aminobutyric acid GAD glutamic acid decarboxylase GAT GABA membrane transporter NMDA N-methyl-D-aspartic acid PV parvalbumin Notes Disclosure/conflict of interest: David A.