Sensitive and specific measures of optic nerve function are vital for detecting and monitoring optic neuropathies and other diseases characterized by inner retinal dysfunction. The full-field flash electroretinogram (ERG) is an established noninvasive tool that records summed electrical activities of retinal neurons and can be measured serially in subjects to evaluate longitudinal changes. While ERG responses derived from photoreceptors and bipolar cells are well characterized, the smaller contributions from innermost cells of the retina, namely, retinal ganglion cells (RGCs), are less well defined.
The photopic negative response (PhNR) is a corneal negative potential after the b-wave of the photopic ERG that was first identified in 1999 by Viswanathan et al.
1 There is good evidence that the PhNR signal originates directly from the spiking activity of RGCs or through mediation by amacrine cells or glia. Studies in rodents and primates have shown reduced PhNR amplitudes in response to optic nerve transection,
2 pharmacological blockage of inner retinal signaling,
1–3 and laser-induced ocular hypertension (OHT)
1 in correlation with RGC loss.
2 There is also evidence that the PhNR can be used to detect inner retinal dysfunction in humans with ocular pathologies of varying etiology. Reduced PhNR amplitudes were seen in patients with open-angle glaucoma,
4–7 optic nerve atrophy,
8 anterior ischemic optic neuropathy,
3 autosomal dominant optic atrophy,
9 and diabetic retinopathy.
6 The magnitude of PhNR signals in patients with inner retinal pathology significantly correlated with clinical parameters and nerve fiber layer thickness.
4,5 Because the PhNR is reduced when visual sensitivity losses are still mild, it holds promise as a tool for early detection of disease.
5 Most recently, we showed that IOP lowering improves PhNR amplitudes in a cohort of glaucoma and OHT patients, suggesting that the PhNR can act as a reversible measure of inner retinal function.
10
Despite growing interest in the PhNR and its clinical applications, the PhNR signal has not yet been described in the mouse to our knowledge. Due to well-defined genetics, amenability to genetic manipulation, high fecundity, and low housing costs, the mouse is one of the most commonly used and important animal models in disease research. Hence, the aim of the present study was to characterize the PhNR of the mouse eye in order to establish a common measure of inner retinal health in mouse and human studies. To address this aim, we determined the presence of the PhNR in the normal mouse retina and tested its sensitivity to an inner retinal–specific injury in the form of acute elevation of intraocular pressure (IOP). We examined how pressure-induced changes to the PhNR compare with changes to other ERG responses originating from inner retina, as well as those originating from middle and outer retina. Furthermore, we correlated functional changes after pressure elevation with retinal cell survival and cellular stress responses. Our findings suggest that the PhNR can act as a single measurable end point of inner retinal health in both mouse and human studies.