Dysfunctions in Multiple Interrelated Systems as the Neurobiological Bases of Schizophrenic Symptom Clusters

Abstract

The absence of an animal model that accurately approximates schizophrenia limits current research into the pathophysiology of this disorder. Obviously, the cognitive disturbances associated with schizophrenia are difficult to evaluate in laboratory animals. Nonetheless, animal studies have provided insight into the anatomy and physiology of the brain systems that have been implicated in schizophrenia. These studies also suggest how brain systems may be involved in information processing in normal and pathological conditions. Thus, a careful assessment of the properties and functions of the brain regions suggested to be involved in schizophrenic symptoms has been a primary objective in several laboratories. In this review, we discuss the interactions among the brain regions implicated in schizophrenia-the ventral striatum, prefrontal cortex, hippocampus, and dopamine systems-and provide an integrative model linking altered function in these regions with specific clusters of symptoms of schizophrenia.Key words: Nucleus accumbens, hippocampus, prefrontal cortex, thalamus, dopamine, negative symptoms, positive symptoms, thought disorder. Schizophrenia Bulletin, 24(2):267-283,1998.Schizophrenia is a complex disorder characterized by a profound disturbance of cognitive functions. A major problem in the study of schizophrenia is the diversity of its symptoms, leading to the suggestion that schizophrenia is actually a cluster of diseases. An integrative clinical view was brought up by Liddle, who used factor analysis to segregate symptoms of schizophrenia into three clusters-reality distortion, psychomotor poverty, and disorganization (Liddle et al. 1992fc)-and proposed that dysfunctions in specific brain regions were involved in each cluster of symptoms (Liddle et al. 1992a). This interpretation is reinforced by a number of studies that implicate a variety of structures in the pathophysiology of schizophrenia. These structures include the prefrontal cortex (PFC), medial temporal lobe (including the hippocampus), ventral striatum, and mesolimbic dopamine (DA) system. In this review, we will link information regarding the physiological interactions among these systems with clinical investigations, in an attempt to analyze these symptom clusters from an anatomical perspective.

Glutamatergic input from specific sources influences the nucleus accumbens-ventral pallidum information flow

“…Dysfunctions of this region may be involved in conditions such as schizophrenia, drug addiction and other neuropsychiatric disorders (Koob and Bloom 1988;O'Donnell and Grace 1998). The NAc has two major subregions-the shell and the core-defined by histochemical, electrophysiological, connectivity and cellular criteria (O'Donnell and Grace 1993;Jongen-Relo et al 1994).…”

Thalamocortical Pathfinding Defects Precede Degeneration of the Reticular Thalamic Nucleus in Polysialic Acid-Deficient Mice

“…On the one hand, incomplete polysialylation of NCAM during brain development has been proposed as a mechanism for a predisposition to schizophrenia because it causes defects of cortical connectivity, including internal capsule defects, resembling those seen in schizophrenic patients ). On the other hand, dysfunction of the Rt has been linked to schizophrenia (O'Donnell and Grace, 1998;Sharp et al, 2001;Krause et al, 2003;Behrendt and Young, 2004;Behrendt, 2006;Zikopoulos and Barbas, 2007). Since all connections between thalamus and cortex traverse the Rt, this nucleus is ideally positioned to play a role in feedback control of thalamocortical circuits and sensory gating.…”

Further Evidence that Behavioral Tests and Neuropeptide mRNA and Tissue Level Alterations Can Differentiate between Typical and Atypical Antipsychotic Drugs

“…The prefrontal cortex is an important brain area in schizophrenia research (Knable and Weinberger 1997;O'Donnell and Grace 1998). In animals, antipsychotic treatment causes an induction of immediate early genes in various brain areas including the prefrontal cortex.…”

“…Consequently, antipsychotics which do not induce catalepsy appear unlikely to increase enkephalin biosynthesis (Augood et al 1993;Mijnster et al 1998). Therefore, both behavioral changes and a distinct pattern of gene expression may be used to predict an atypical profile for an antipsychotic compound.The prefrontal cortex is an important brain area in schizophrenia research (Knable and Weinberger 1997;O'Donnell and Grace 1998). In animals, antipsychotic treatment causes an induction of immediate early genes in various brain areas including the prefrontal cortex.…”