Neurochemical and structural prefrontal cortex abnormalities, including decreased reelin and glutamic acid decarboxylase (GAD)(67) expression, decreased thickness, increased neuronal packing density and decreased neuropil and dendritic spine number, are characteristics of schizophrenia neuropathology. Reelin is an extracellular matrix protein secreted by GABAergic interneurons that, acting through pyramidal neuron integrin receptors, provides a signal for dendritic spine plasticity. Heterozygous reeler mice that exhibit a 50% downregulation of reelin expression (mRNA and protein) replicate the dendritic spine and GABAergic defects described in schizophrenia. This genetic mouse model may be of value to reveal those GABAergic and integrin receptor signal transduction mechanisms that are likely to be downregulated by reelin deficiency in the brain of schizophrenia patients. An understanding of the epigenetic regulation of reelin gene expression and of the possible pathogenetic role of reelin deficiency in schizophrenia, may become a major focus that will open new avenues for the treatment of this disease.