FUNCTIONAL AND ANATOMICAL ASPECTS OF PREFRONTAL PATHOLOGY IN SCHIZOPHRENIA

Clinical and experimental research have provided anatomical, pharmacol ogical, and behavioral evidence for a prominent prefrontal dysfunction in schizophrenia. Negative symptoms and behavioral disorganization in the disorder can be understood as a failure in the working memory fun ctions of the prefrontal cortex by which information is updated on a m oment-to-moment basis or retrieved from long-term stores, held in mind , and used to guide behavior by ideas, concepts, and stored knowledge, This article recounts efforts to dissect the cellular and circuit bas is of working memory with the goal of extending the insights gained fr om the study of normal brain organization in animal models to an under standing of the clinical disorder; it includes recent neuropathologica l findings that indicate that neural dystrophy rather than cell loss p redominates in schizophrenia, Evidence from a variety of studies is ac cumulating to indicate that dopamine has a major role in regulating th e excitability of the cortical neurons upon which the working memory f unction of the prefrontal cortex depends, Interactions between monoami nes and a compromised cortical circuitry may hold the key to the salie nce of frontal lobe symptoms in schizophrenia, in spite of widespread pathological changes, We outline several direct and indirect intercell ular mechanisms for modulating working memory function in the prefront al cortex based on the localization of dopamine receptors on the dista l dendrites and spines of glutamatergic pyramidal cells and on gamma-a minobutyric acid (GABA)ergic interneurons in the prefrontal cortex, Un derstanding the interactions between the major cellular constituents o f cortical circuits-pyramidal and nonpyramidal cells-is a necessary st ep in unraveling the receptor mechanisms, which could lead to an effec tive pharmacological treatment of negative and cognitive symptoms, as well as improved insight into the pathophysiological basis of the diso rder.