Restoration of visual performance by d -serine in models of inner and outer retinal dysfunction assessed using sweep VEP measurements in the conscious rat and rabbit

Abstract

The NMDA subtype of glutamate receptor and its co-agonist d-serine play a key role in synaptic function in the central nervous system (CNS), including visual cortex and retina. In retinal diseases such as glaucoma and macular degeneration, a loss of vision arises from malfunction of retinal cells, resulting in a glutamate hypofunctional state along the visual pathway in the affected parts of the visual field. An effective strategy to remedy this loss of function might be to increase extracellular levels of d-serine and thereby boost synaptic NMDA receptor-mediated visual transmission and/or plasticity to compensate for the impairment. We tested this idea in brain slices of visual cortex exhibiting long-term potentiation, and in rodent models of visual dysfunction caused by retinal insults at a time when the injury had stabilized to look for neuroenhancement effects. An essential aspect of the in vivo studies involved adapting sweep VEP technology to conscious rats and rabbits and combining it with intracortical recording while the animals were actively attending to visual information. Using this technology allowed us to establish complete contrast sensitivity function curves. We found that systemic d-serine dose-dependently rescued the contrast sensitivity impairment in rats with blue light-induced visual dysfunction. In rabbits with inner retinal dysfunction, both systemic and intravitreal routes of d-serine provided a rescue of visual function. In sum, we show that co-agonist stimulation of the NMDA receptor via administration of exogenous d-serine might be an effective therapeutic strategy to enhance visual performance and compensate for the loss of vision resulting from retinal disease.

Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction

“…We have previously reported that rats exposed to blue light have long-lasting and stable deficits in contrast sensitivity that can be acutely improved by systemic administration of D-serine (Staubli et al, 2016). In the current experiments, a group of rats was used 53 weeks after blue light exposure that had a stable contrast sensitivity deficit of approximately 6 (Fig.…”

“…Effects of PG Analogs in Models of Visual Function. Since we have previously shown that systemically applied D-serine can have beneficial effects on visual function (Staubli et al, 2016), L-4FPG and L-4OHPG were tested in naive rats for their ability to influence normal vision (Fig. 6).…”

“…In the current experiments, a group of rats was used 53 weeks after blue light exposure that had a stable contrast sensitivity deficit of approximately 6 (Fig. 6C); values for rats with intact vision under these experimental conditions were approximately 10 (Staubli et al, 2016). Administration of a single dose of L-4FPG (10 mg/kg, i.p.)…”

“…The methods were described in a previous article (Staubli et al, 2016). The recording electrodes were permanently implanted into the right visual cortex of Long-Evans rats at lambda and 4.5 mm lateral to the midline, to a depth of 800 mm (layer III/IV).…”

“…Subsequently, the administration of the NMDA receptor coagonist D-serine was shown to relieve schizophrenic symptoms in patients when coadministered with antipsychotic agents (Heresco-Levy et al, 2005;Kantrowitz et al, 2010), presumably by restoring NMDA receptor tone. In the visual system, NMDA receptors are important for responses along the visual pathway (Hartveit and Heggelund, 1990;Scharfman et al, 1990;Simon et al, 1992;Stevens et al, 2003), and we have shown previously that the administration of D-serine can restore visual performance impaired by retinal degeneration (Staubli et al, 2016). Consequently, therapies based on restoring NMDA receptor tone may be effective in relieving schizophrenia symptoms and restoring visual function after retinal degeneration.…”