The quantitative neuropathology of schizophrenia

Abstract

Schizophrenia is a devastating neuropsychiatric disorder showing a variety of cognitive disturbances in attention, working memory, verbal production, response monitoring and inhibition, in short, almost all aspects of information processing and evaluation. Equally diverse are the putative mechanisms that translate such deWcits into the anatomical substrates of schizophrenia pathology. Alterations in brain wiring and connectivity have long been suspected to play a key role in the development of schizophrenia. The resulting disorganization of neuronal systems in speciWc regions of the cerebral cortex and in certain subcortical structures may represent an anatomic and functional substrate for the constellation of symptoms that are typically observed in schizophrenic patients. To date, many studies have reported consistent and at times severe changes in the gray matter in schizophrenia and have paid attention to the connectivity of speciWc subsystems and particular populations of neurons. Reported abnormalities concern not only the numbers or densities of neurons but also their local microcircuitry and their distribution. Thus, altered densities and distribution of various populations of neurons have been reported in the prefrontal cortex in schizophrenia. Subclasses of interneurons are known to display abnormal localization in the subcortical white matter of the prefrontal cortex suggestive of cortical developmental pathology. Other data point to alterations of calretinin-containing interneurons, abnormal axonal terminals from inhibitory neurons, reduced gene expression of markers of inhibitory neurons, and to pathology of chandelier neuron axons endings on pyramidal cells in the prefrontal cortex of schizophrenic patients. Neuronal packing densities have been shown to be elevated in the prefrontal cortex of schizophrenic cases with a severe reduction in size of large layer III pyramidal cells, indicating that profound cellular attrition occurs during the progression of the disease. It has been proposed that such pathology of large projection neurons could be the result of altered inhibitory activity and an expression of excitotoxic damage. Comparable changes have been reported in the entorhinal cortex with abnormalities in neuronal distribution within the layer II clusters, as well as dendritic alterations, cell size reduction, and in certain subdomains of the entorhinal cortex, lower neuronal densities. A deWcit in synaptic transmission has also been suggested in schizophrenia based on reduced synaptophysin immunoreactivity in the prefrontal cortex as well as a severe impoverishment of the dendritic structure of pyramidal neurons and loss of dendritic spines. Finally, the thalamus has been the object of many studies of neuronal numbers showing that schizophrenia is accompanied by a variable loss of neurons at the nucleus or subnucleus level, suggesting a certain degree of regional speciWcity in the pathology that may diVerentially aVect speciWc sets of connections to the prefrontal cortex. It is worth noting that these alterations are speciWc to certain neural systems, as many regions of the brain do not show such changes. The concept of disrupted connectivity and abnormal synaptic transmission is key to our understanding of the cognitive and psychotic symptoms in schizophrenia. The involvement of the thalamoprefrontal pathway, together with the morphological alterations of prefrontal pyramidal P. R. Hof (&) · C. Schmitz Department of Neuroscience, Mount Sinai School of Medicine, Box 1065, One Gustave L. Levy Place, New York, NY 10029, USA e-mail: patrick.hof@mssm.edu