Biology subjects

Grimes, W. N.

Publications and source records attributed to Grimes, W. N..

4 recordsLinked to original sources

bioRxiv2024

A metabotropic glutamate receptor agonist enhances visual signal fidelity in a mouse model of retinitis pigmentosa

Many inherited retinal diseases target photoreceptors, which transduce light into a neural signal that is processed by the downstream visual system. As photoreceptors degenerate, physiological and morphological changes to retinal synapses and circuitry reduce sensitivity and increase noise, degrading visual signal fidelity. Here, we pharmacologically targeted the first synapse in the retina in an effort to reduce circuit noise without sacrificing visual sensitivity. We tested a strategy to partially replace the neurotransmitter lost when photoreceptors die with an agonist of receptors that ON bipolars cells use to detect glutamate released from photoreceptors. In rd10 mice, which express a photoreceptor mutation that causes retinitis pigmentosa (RP), we found that a low dose of the mGluR6 agonist L-2-amino-4-phosphonobutyric acid (L-AP4) reduced pathological noise induced by photoreceptor degeneration. After making in vivo electroretinogram recordings in rd10 mice to characterize the developmental time course of visual signal degeneration, we examined effects of L-AP4 on sensitivity and circuit noise by recording in vitro light-evoked responses from individual retinal ganglion cells (RGCs). L-AP4 decreased circuit noise evident in RGC recordings without significantly reducing response amplitudes, an effect that persisted over the entire time course of rod photoreceptor degeneration. Subsequent in vitro recordings from rod bipolar cells (RBCs) showed that RBCs are more depolarized in rd10 retinas, likely contributing to downstream circuit noise and reduced synaptic gain, both of which appear to be ameliorated by hyperpolarizing RBCs with L-AP4. These beneficial effects may reduce pathological circuit remodeling and preserve the efficacy of therapies designed to restore vision. Significance StatementRetinitis Pigmentosa (RP) is an inherited degenerative disease that affects more than two million people worldwide. RP patients first lose peripheral and low-light vision due to the progressive death of their highly sensitive rod photoreceptors. Photoreceptor degeneration induces pathological noise within the retinal circuit, leading to dramatic structural changes that may hamper therapies to restore visual sensitivity. We discovered a pharmacological treatment that reduces pathological activity in a mouse model of RP without diminishing signaling in surviving circuitry. Partially replacing the neurotransmitter lost when photoreceptors die reduced noise in the retinal circuit without eliminating light sensitivity. This approach could limit the impact of the disease on retinal neurons and preserve the efficacy of subsequent restorative therapies.

neuroscience↗

bioRxiv2020

A high-density narrow-field inhibitory retinal interneuron with direct coupling to Müller glia

Amacrine cells are interneurons comprising the most diverse cell type in the mammalian retina. They help encode visual features such as edges or directed motion by mediating excitatory and inhibitory interactions between input (i.e. bipolar) and output (i.e. ganglion) neurons in the inner plexiform layer (IPL). Like other brain regions, the retina also contains glial cells that contribute to neurotransmitter uptake, neurovascular control and metabolic regulation. Here, we report that a previously poorly characterized, but relatively abundant, inhibitory amacrine cell type in the mouse retina is coupled directly to Muller glia. Electron microscopic reconstructions of this amacrine type revealed extensive associations with Muller glia, whose processes often completely ensheathe the neurites of this amacrine cell type. Microinjections of small tracer molecules into the somas of these amacrine cells led to selective labelling of nearby Muller glia, leading us to suggest the name "Muller glia-coupled amacrine cell" or MAC. Our electrophysiological data also indicate that MACs release glycine at conventional chemical synapses with amacrine, bipolar and retinal ganglion cells (RGCs), and viral transsynaptic tracing showed connections to several known RGC types. Visually-evoked responses revealed a strong preference for light increments; these "ON" responses were primarily mediated by excitatory chemical synaptic input and direct electrical coupling to other cells. This initial characterization of the MAC provides the first evidence for neuron-glia coupling in the mammalian retina and identifies the MAC as a potential link between inhibitory processing and glial function. Significance StatementGap junctions between pairs of neurons or glial cells are commonly found throughout the nervous system, and play a myriad of roles including electrical coupling and metabolic exchange. In contrast, gap junctions between neurons and glia cells are rare and poorly understood. Here we report the first evidence for neuron-glia coupling in the mammalian retina, specifically between an abundant (but previously unstudied) inhibitory interneuron and Muller glia.

neuroscience↗

bioRxiv2019

Rod-cone signal interference in the retina shapes perception in primates

Linking the activity of neurons, circuits and synapses to human behavior is a fundamental goal of neuroscience. Meeting this goal is challenging, in part because behavior, particularly perception, often masks the complexity of the underlying neural circuits, and in part because of the significant behavioral differences between primates and animals like mice and flies in which genetic manipulations are relatively common. Here we relate circuit-level processing of rod and cone signals in the non-human primate retina to a known break in the normal seamlessness of human vision - a surprising inability to see high contrast flickering lights under specific conditions. We use electrophysiological recordings and perceptual experiments to identify key mechanisms that shape the retinal integration of rod- and cone-generated retinal signals. We incorporate these mechanistic insights into a predictive model that accurately captures the cancellation of rod- and cone-mediated responses and can explain the perceptual insensitivity to flicker.

neuroscience↗

bioRxiv2018

Rod signaling in primate retina: range, routing and kinetics

Stimulus or context dependent routing of neural signals through parallel pathways can permit flexible processing of diverse inputs. For example, work in mouse shows that rod photoreceptor signals are routed through several retinal pathways, each specialized for different light levels. This light level-dependent routing of rod signals has been invoked to explain several human perceptual results, but it has not been tested in primate retina. Here we show, surprisingly, that rod signals traverse the primate retina almost exclusively through a single pathway, regardless of light level. Indeed, identical experiments in mouse and primate reveal large differences in how rod signals traverse the retina. These results require reevaluating human perceptual results in terms of flexible computation within this single pathway. This includes a prominent speeding of rod signals with light level - which we show is inherited directly from the rods photoreceptors themselves rather than from different pathways with different kinetics.

neuroscience↗