New neurochemical markers for psychosis: A working hypothesis of their operation

Reelin (Reln) is expressed in specific GABAergic neurons in layer I and II of neocortex, and is secreted into the extracellular matrix where it surrou nds dendrites, spines and neurite arborizations, and binds to integrin rece ptors located on post-synaptic densities of apical dendritic spines. Experi ments in rodents (including wild type or reeler heterozygous mice) and non- human primates suggest the Rein secreted in the extracellular matrix of neo cortex, via integrin receptors, modulates the function of the adaptor prote in DAB1 (drosophila disable-gene) homologous product) thereby participating in dynamic processes associated with plasticity changes in dendrites, dend ritic spines and their synapses. A local protein synthesis at dendritic spi nes (ie the activity regulated cytoskeleton associated protein, Arc) probab ly acts as a signal for plastic modulatory activities in synapses operative in neural group interactions. A research strategy directed toward identify ing specific neurochemical markers operative in the etiopathology of psycho tic disorders lead to the identification of a downregulation (30-50%) of Re in and glutamic acid decarboxylase 67(GAD67) expression in prefrontal corte x and other brain areas of schizoprenia and bipolar disorder patients with psychosis. These downregulations were not due to neuronal damage, postmorte m interval, or antipsychotic medication. The dysfunction of GABAergic inter neurons observed in psychotic brains in combination with reduced Rein expre ssion and downregulation of Reln-integrin receptor interaction, may provide an explanation for the reported decrease in neuropile expression including dendritic spine density reduction, in neocortex of schizophrenia patients. This downregulation of neuropile plasticity may be a factor to be consider ed in the etiology of the disintegration of consciousness, which is one of the primary signs of psychosis.