Effects of D-serine treatment on outer retinal function.

The role of the N-Methyl-D-Aspartate Receptor (NMDAR) in the outer retina is unclear despite expression of the NMDAR-complex and its subunits in the outer retina. The flash-electroretinogram (fERG) offers a non-invasive measurement of the retinal field potentials of the outer retina that can serve to clarify NMDAR contribution to early retinal processing. The role of the NMDAR in retinal function was assessed using a genetic mouse model for NMDAR hypofunction (SR-/-), where the absence of the enzyme serine racemase (SR) results in an 85% reduction of retinal D-serine. NMDAR hypo- and hyperfunction in the retina results in alterations in the components of the fERG. The fERG was examined after application of exogenous D-serine to the eye in order to determine whether pre- and post-topical delivery of D-serine would alter the fERG in SR-/- mice and their littermate WT controls. Amplitude and implicit time of the low-frequency components, the a- and b-wave, were conducted. Reduced NMDAR function resulted in a statistically significantly delayed a-wave and reduced b-wave in SR-/- animals. The effect of NMDAR deprivation was more prominent in male SR-/- mice. A hyperfunction of the NMDAR, through exogenous topical delivery of 5 mM D-serine, in WT mice caused a significantly delayed a-wave implicit time and reduced b-wave amplitude. These changes were not observed in female WT mice. There were temporal delays in the a-wave and amplitude and a decrease in the b-wave amplitude and implicit time in both hypo- and NMDAR hyperfunctional male mice. These results suggest that NMDAR and D-serine are involved in the retinal field potentials of the outer retina that interact based on the animal's sex. This implicates the involvement of gonadal hormones and D-serine in retinal functional integrity.

Electroretinographic Abnormalities and Sex Differences Detected with Mesopic Adaptation in a Mouse Model of Schizophrenia: A and B Wave Analysis.

Purpose: Mesopic flash electroretinography (fERG) as a tool to identify N-methyl-d-aspartate receptor (NMDAR) hypofunction in subjects with schizophrenia shows great potential. We report the first fERG study in a genetic mouse model of schizophrenia characterized by NMDAR hypofunction from gene silencing of serine racemase (SR) expression (SR-/-), an established risk gene for schizophrenia. We analyzed fERG parameters under various background light adaptations to determine the most significant variables to allow for early identification of people at risk for schizophrenia, prior to onset of psychosis. SR is a risk gene for schizophrenia, and negative and cognitive symptoms antedate the onset of psychosis that is required for diagnosis. Methods: The scotopic, photopic, and mesopic fERGs were analyzed in male and female mice in both SR-/- and wild-type (WT) mice and also analyzed for sex differences. Amplitude and implicit time of the a- and b-wave components, b-/a-wave ratio, and Fourier transform analysis were analyzed. Results: Mesopic a- and b-wave implicit times were significantly delayed, and b-wave amplitudes, b/a ratios, and Fourier transform were significantly decreased in the male SR-/- mice compared to WT, but not in female SR-/- mice. No significant differences were observed in photopic or scotopic fERGs between genotype. Conclusions: The fERG prognostic capability may be improved by examination of background light adaptation, a larger array of light intensities, considering sex as a variable, and performing Fourier transform analyses of all waveforms. This should improve the ability to differentiate between controls and subjects with schizophrenia characterized by NMDAR hypofunction.

Electoretinographic evidence of retinal ganglion cell-dependent function in schizophrenia.

Schizophrenia is a complex disorder that is diagnosed mainly with clinical observation and evaluation. Recent studies suggest that many people with schizophrenia have abnormalities in the function of the N-methyl-d-aspartate receptor (NMDAR). The retina is part of the central nervous system and expresses the NMDAR, raising the possibility of the early detection of NMDAR-related schizophrenia by detecting differences in retinal function. As a first-step, we used two non-invasive outpatient tests of retinal function, the photopic negative response (PhNR) of the light-adapted flash-electroretinogram (PhNR-fERG) and the pattern ERG (PERG), to test individuals with schizophrenia and controls to determine if there were measurable differences between the two populations. The PhNR-fERG showed that males with schizophrenia had a significant increase in the variability of the overall response, which was not seen in the females with schizophrenia. Additionally at the brightest flash strength, there were significant increases in the PhNR amplitude in people with schizophrenia that were maximal in controls. Our results show measurable dysfunction of retinal ganglion cells (RGCs) in schizophrenia using the PhNR-fERG, with a good deal of variability in the retinal responses of people with schizophrenia. The PhNR-fERG holds promise as a method to identify individuals more at risk for developing schizophrenia, and may help understand heterogeneity in etiology and response to treatment.