Regional abnormalities of brain connectivity may be an important substrate for the expression of schizophrenia, a severe form of mental illness. Brain imaging and postmortem morphometric studies indicate hippocampal structure is abnormal in schizophrenia. To study molecular components of hippocampal connectivity the presynaptic proteins SNAP-25 and synaptophysin were assayed in postmortem samples. Immunocytochemical studies indicated reduced SNAP-25 immunoreactivity in schizophrenia compared to controls, particularly in the terminal fields of entorhinal cortex projections. Although there were no overall changes in synaptophysin immunoreactivity, in the granule cell layer of the dentate gyrus synaptophysin immunoreactivity was increased in schizophrenia. These results indicate that disconnection of a subset of hippocampal circuitry from the entorhinal cortex, as well as intrinsic changes in hippocampal connectivity, may contribute to the mechanism of illness in schizophrenia.