The Role Of D-Serine In Normal Retinal Function And Implications For Psychiatry

Abstract

There is a lack of objective measurements for assessing the progression of mental disorders such as schizophrenia. Biomarkers for schizophrenia would be an invaluable asset to identify at-risk individuals objectively, which should consequently improve the person’s prognosis and treatment. One such candidate for becoming a biomarker for schizophrenia is the flash-electroretinogram (fERG), an ophthalmological tool that assesses retinal integrity. Prior research had conflicting results, with some studies showing that people with schizophrenia have a reduced response from photoreceptors and bipolar cells. However, it has been unclear why abnormalities would occur that early in the retinal pathway when mouse studies that investigated monoamine deprivation, such as dopamine, did not reflect those deficits. An alternative reason for an altered fERG is that it may reflect reduced N-methyl-d-aspartate receptor (NMDAR) function, which has been postulated to explain some of the pathology exhibited in people with schizophrenia. However, no retinal field potentials in the outer retina had been attributed to NMDAR function. One way to induce hypofunction of the NMDAR is by reducing the availability of its co-agonist, either glycine or D-serine, since the NMDAR needs both glutamate and a co-agonist for activation. I examined how D-serine deprivation and its excess affects the outer retinal field potentials, and whether it has implications for psychiatry. We report the first fERG study in a genetic mouse model of schizophrenia characterized by NMDAR hypofunction from genetic silencing of serine racemase expression (SR-/-), an enzyme that converts L-serine to D-serine. We analyzed fERG components under mesopic-adapted conditions that reflect outer retinal function, the a-wave and the b-wave, to determine the resemblance to the human fERG from people with schizophrenia. In all the analyses, I included sex as a factor, due to thevii sex differences underlying the disease. We tested pharmacologically-induced hyperfunction of the NMDAR in WT mice by introducing D-serine. Lastly, we analyzed human fERG and pattern-electroretinogram (PERG) studies to assess outer and inner retinal function. I report that hypo- or hyper-function of the NMDAR, through changes in available D-serine, profoundly affects the temporal scale of photoreceptor and bipolar cell signaling, as well as the amplitude of bipolar cell currents. This work mirrors the deficits observed in people with schizophrenia. Including sex as a factor in analyses showed that D-serine affects male mice more profoundly regardless of genotype, suggesting that NMDAR and D-serine are involved in the retinal field potentials of the outer retina and are dependent on the animal’s sex. These studies also suggest that either there is a functional NMDAR component to the outer retinal field potentials or that D-serine has another role in the retina aside from being an endogenous co-agonist for the NMDAR. This implicates the involvement of gonadal hormones and D-serine in retinal functional integrity. Our human analyses reflect deficits in the retinal ganglion cell layer, and a trending reduction of the signal corresponding to bipolar cells. Furthermore, the human data analyses also showed an interaction between sex, with deficits affecting males with schizophrenia more profoundly. This work elevates the potential of the fERG to differentiate between healthy controls and subjects with schizophrenia, and to detect sex differences known to be present in schizophrenia