Schizophrenia is a chronic disruptive disease that affects 1% of the population. Current treatment only relieves symptoms but does not cure the disease. Unfortunately, the exact cause of schizophrenia is not known. Throughout the years there have been multiple hypotheses for schizophrenia, one of which arrived from clinical studies of dissociative anesthetics that imitate the negative symptoms (disruption to emotional and behavioral states), cognitive impairments, and brain abnormalities associated with schizophrenia. Since these dissociative anesthetics antagonize a subclass of glutamate receptors called NMDA receptors, it is postulated that like the drugs, schizophrenia results from hypoactivity of the NMDA receptor. Interestingly, some schizophrenic patients have a deficiency of D-serine, a co-agonist of the NMDA receptor. When treated with D-serine, schizophrenic symptoms improve. By using a variation of the electroretinogram (ERG), known as the pattern- ERG, or pERG, we can measure NMDA-mediated activity that is evoked by light in retinal ganglion cells. This application seeks to understand how different levels of D-serine determine the conditions under which the pERG signal reveals an NMDA receptor component in the retina. We hypothesize that a reduction in D-serine reflects the NMDAR hypofunction found in schizophrenic patients, and that the lack of D-serine impacts the expression of NMDA receptors in the retina such that abnormities can be observed from pERG.
The first aim of this study is to pharmacologically reduce and enhance the activity of NMDA receptors with antagonists to evaluate the NMDA component of the pERG. This will be conducted by extracellular recording from isolated perfused retina eye-cups from normal, D-serine deprived, and D-serine elevated mice.
The second aim of this study is evaluate the mouse pERG and compare it to the human schizophrenic and normal controls pERG responses. The proposed study directly tackles the NMDAR hypofunction hypothesis for schizophrenia. It embarks in a new way to look at schizophrenia by using signals from the eye that can demonstrate NMDA signaling deficiency hypothesized to account for schizophrenia. Furthermore, these studies in D-serine function will contribute to the current knowledge of the etiology of the disease;which fits directly with the NIMH strategic plan of prevention and treatment for schizophrenia. The public health impact is in understanding the etiology of the disease and improving the diagnostic tools for schizophrenia by using non-invasive signals from the eye, the pERG.
This research project presents a new way to diagnose schizophrenia by using signals from the eye that are referred to as the pERG (pattern-electroretinogram). We propose that the pERG has an N-methyl-D-aspartate receptor (NMDAR) component that can reflect the postulated abnormalities in NMDAR function in people affected by schizophrenia. Since the pERG can be easily obtained in humans by placing electrodes on the cornea of the eye and presenting a pattern image, this non-invasive technique can serve as a diagnostic tool for the disease.