In a previous study, we found a profound loss of spines on the apical dendrites of pyramidal neurons in the left subiculum of individuals with schizophrenia, with no overlap between subjects with schizophrenia and those without psychiatric illness. In addition, there was a significant reduction in the apical dertdritic arbors of these cells, but not in their basilar dendritic arbors, nor in the dendritic arbors of pyramidal neurons in the adjacent neocortex. Since completing that study, we have improved our technique for rapid Golgi staining, so that it is now applicable to tissue from the pre-neuroleptic era, that has been in lormalin for over 50 years. Furthermore, the number of Golgi-impregnated neurons is now sufficient to permit random sampling of neurons for evaluation. Similar findings by other researchers who examined other regions of the brain, and our own data showing abnormalities of subicular MAP2, supporting diminished cognitive reserve, and documenting the longitudinal course of cognitive and clinical deterioration, all support the notion of decreased synaptic connectivity as a substrate for schizophrenia. We now propose to employ improved Golgi staining to study 5 groups of 20 individuals in order: (1) To evaluate the replicability of our previous finding. (2) To determine whether similar abnormalities are present in archived brains from schizophrenia patients who died before the introduction of neuroleptic drugs. It is possible that these drugs induce the loss of spines, that they protect against it, or that they do neither. (3) To determine whether similar abnormalities are present in the brains of young schizoprhenia subjects, which will help to determine whether the loss of spines is more likely a cause or a result of schizophrenia, and whether it is progressive. (4) To evaluate prefrontal cortex, primary visual cortex, and additional areas of hippocampus, in order to determine whether spine loss in schizoprhenia is localized or generalized.
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