Michael Telias, PhD
Postdoc in Richard Kramer's Lab
Monday, February 4, 2019
11:10 am - 12:30 pm
489 Minor Hall
Retinoic acid is the trigger for neural hyperactivity in retinal degeneration and
blocking its receptor unmasks light responses and augments vision
Light responses are initiated in photoreceptors, processed by interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information to the brain. Retinitis pigmentosa (RP) is a blinding disease caused by photoreceptor degeneration, depriving downstream neurons of light-sensitive input. In addition, photoreceptor degeneration triggers hyperactive firing of RGCs that obscures light responses initiated by surviving photoreceptors. Here we show that retinoic acid (RA), signaling through its receptor (RAR), is the trigger for hyperactivity. A genetically encoded fluorescent reporter shows elevated RAR signaling in degenerated retinas from murine models of RP. Enhancing RAR signaling in healthy retinas mimics the pathophysiology of degenerating retinas. Drug inhibition of RAR reduces hyperactivity in degenerating retinas and unmasks light responses in RGCs. Gene therapy inhibition of RAR increases innate and learned light-elicited behaviors in vision-impaired mice. Identification of RAR as the trigger for hyperactivity presents a degeneration-dependent therapeutic target for enhancing low-level vision in RP and other blinding disorders.
Understanding a Wide-field Amacrine Cell’s Role in Shaping Retinal Output
The output cells of the retina, ganglion cells, are a broad group of about 40 neuron types, each tuned to a specific feature of the visual scene. For example, the W3 ganglion cell, known as a local motion detector, responds strongly in response to small objects moving across a static background, but is silent during global motion. Ganglion cell receptive fields are shaped by inhibitory interneurons called amacrine cells. In this study we test how a GABAergic amacrine cell—defined by its wide-field morphology and identified by a transgenic mouse line (nNOS-Cre-ER)—is functioning to inhibit ganglion cells, such as the W3 cell. We predict that this NOS expressing amacrine cell provides direct GABAergic inhibition to the W3 ganglion cell in a way that lends it the ability to only respond to small stimuli.