Abstract
Purpose :
The visual system requires stable encoding of environmental illuminance across a wide dynamic range. Illuminance is encoded within the retina by the M1 subclass of intrinsically photosensitive retinal ganglion cells (M1 ipRGCs). M1 ipRGCs integrate extrinsic signals from photoreceptors with their own intrinsic light responses to drive non-image-forming (NIF) behaviors such as the pupillary light reflex (PLR) and circadian photoentrainment. This integration is vital for illuminance encoding and downstream NIF behaviors; however, it is unknown whether the M1 ipRGC circuit can compensate for perturbations to its synaptic input. In perturbed circuits, homeostatic plasticity can restore neural activity and preserve functional stability. However, it is unclear how and to what extent homeostatic plasticity can restore activity in the highly specialized M1 ipRGC circuit and preserve NIF behaviors at the level of the entire organism.
Methods :
To address this question, we used mice in which the type 6 bipolar cell (B6), which provides ~90% of the synaptic input to M1 ipRGCs, was genetically deleted through targeted expression of diphtheria toxin (DTA; B6-DTA mice). We recorded the PLR and circadian rhythms of B6-DTA and control mice under different illuminance regimes to analyze the extent, if any, of homeostatic compensation. Additionally, we performed immunohistochemical assays to confirm B6 deletion and electrophysiological experiments to investigate the B6 to M1 ipRGC synapse.
Results :
First, we expand upon previous structural evidence to show that type 6 bipolar (B6) cells functionally provide extrinsic photoreceptor-derived input to M1 ipRGCs. We find preserved PLR magnitude, sensitivity, and kinetics in B6-DTA mice. Using a novel stimulus paradigm to isolate the extrinsic component of the PLR, we found only subtle changes in pupil responses for B6-DTA mice. Furthermore, B6-DTA mice were able to successfully photoentrain their circadian rhythms across a broad range of light levels.
Conclusions :
We demonstrate that homeostatic plasticity preserves NIF vision via compensatory rewiring of non-canonical synaptic input to M1 ipRGCs. The mechanisms by which this plasticity is accomplished could reveal fresh insights into both the biology of retinal illuminance-detection circuits as well as novel strategies to preserve visual behaviors after injury.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.