Sleep disturbances, eye movement abnormalities, attentional deficits, locomotor abnormalities and other features of the schizophrenic syndrome implicate structures within a brain region termed the mesopontine reticular formation. A comprehensive study of the reticular formation in post mortem brain tissue from deceased patients with schizophrenia is proposed. Tissue for comparison purposes will be obtained from subjects with other psychiatric disorders and normal controls. A successful system for the collection of post mortem brain tissue has been established. Cholinergic and catecholaminergic nuclei of the reticular formation will be studied using immunocytochemical and histochemical methods. Using computer assisted image analysis, preliminary results suggest that, in schizophrenia, there are increased numbers of neurons in the pedunculopontine nucleus, a cholinergic nucleus of the reticular formation. The size of neurons in the locus coeruleus, a catecholaminergic nucleus of reticular formation, is reduced. One aim of this proposal is to substantiate these findings in additional patients. As neuronal number is determined during development, this data may be consistent with a neurodevelopmental basis of schizophrenia. Etiology (neurodevelopment versus neurodegeneration) will be probed further through studies of the relevant proteins and the mRNAs that express them. Our preliminary results derived from Western immunoblot studies of brain tissue suggest that the concentrations of the structural proteins of glia are not increased in schizophrenia. This absence of gliosis, the hallmark of neurodegeneration, as measured by this quantitative technique, suggests that schizophrenia does not result from neurodegeneration. We have found a relatively low concentration of the developmentally regulated protein, beta-tubulin, in the brain stem which is again consistent with a neurodevelopmental malfunction in schizophrenia. The second aim of this proposal is to extend this work.