This research project is designed to provide new methods for revealing and studying patients with psychiatric diseases with special emphasis on the root causes of schizophrenia. We are proposing a new way of evaluating schizophrenic patients based on a simple ophthalmological recording technique known as the electroretinogram or ERG. The ERG is an electrical signal routinely and non-invasively recorded from the front of the eye and is a common procedure found in most ophthalmological clinics. We propose that a variant of the conventional ERG, called the pattern ERG or pERG reflects activity of retinal ganglion cells and has a signature response component that can be attributed to light-evoked activity of N-methyl-D-Aspartate or NMDA receptors (NMDARs). Abnormal regulation of NMDARs has been implicated as one cause of schizophrenia and this project will definitively evaluate this possibility. Indeed, we hav obtained preliminary data from four schizophrenic patients in which the pERG is characteristically different than that recorded from normal controls. When we compare the schizophrenic pERG with the mouse pERG, recorded from an isolated, perfused retina preparation, the mouse pERG looks very much like the control human subjects, but when the retina is perfused with an antagonist that eliminates the contribution of NMDA receptors to the pERG, the resulting waveform looks strikingly similar to the pERG observed in schizophrenic patients. These remarkable findings have stimulated the current application, with the broad objective of recording from a wider sampling of patients, including schizophrenics that have not received anti-psychotic medication to insure that we are not observing a drug effect in pERG recordings from schizophrenic patients. The strategy behind this research is to use the pERG to study human patients with schizophrenia and compare them with age- and gender-matched controls. We will evaluate cognitive functions of each human subject through testing procedures and carry out separate experiments in mice to determine how NMDARs contribute to the pERG response. In addition, we plan to carry out experiments in which mice have been maintained on antipsychotic medication for acute and chronic periods. We will also use the mouse preparation to refine our pERG stimulation parameters to optimize for the NMDA receptor contribution and modify accordingly the visual stimulus we use for human subjects. We expect that this study will definitively address the question of NMDA receptor involvement in schizophrenic patients.
This project is designed to develop new ways, based on non-invasive electrical recordings from the human eye, to provide fresh insights into the origins of psychiatric diseases, with a special emphasis on schizophrenia. Our preliminary results with recordings from schizophrenic patients and normal subjects indicate that the strategy developed in this application will reveal new insights into the origins of this disease and thereby open a new window for therapeutic strategies and more comprehensive analysis.