Abstract
Purpose :
Proper transmission of visual information relies on neurons forming appropriate synaptic connections to their respective targets during development. In the outer retina, photoreceptors are the main detectors of lights that synapse selectively to distinct partners. Cone photoreceptors synapse to the dendrites of horizontal cells and to the dendrites of cone bipolars, whereas rod photoreceptors synapse to the axon of horizontal cells and to the dendrites of rod bipolars. The molecular mechanisms that guide selective wiring of photoreceptors to their distinct targets remains poorly understood.
Methods :
Our initial data identified the L1 cell adhesion molecule Neurofascin (Nfasc) to be localized in the developing synaptic layer and exclusively expressed in rods, horizontal cells, and rod bipolars. Moreover, other cell adhesion molecules (i.e. Cntn1, Caspr, Nrcam) that are known to work alongside Nfasc are expressed in the complementary cone pathway. Based on these data, we hypothesize that restricted expression of cell adhesion molecules mediates selective wiring of photoreceptors to their respective targets. To test our hypothesis, we perform loss- and gain-of-function experiments using mouse transgenics, in vivo genetic manipulations, and single neuron labeling approaches.
Results :
We found that disruption of Nfasc leads to synaptic defects affecting rod connectivity but not cone connectivity. These include loss of pre- and post-synaptic protein expression among rods and rod bipolars as well as a decrease in rod-driven visual responses. However, synaptic connections among cones and cone bipolars do not appear to be affected. Moreover, ectopic expression of the cone-restricted cell adhesion molecule, Nrcam in rods results in rod terminals projecting deeper and making aberrant contacts to cone bipolars. These data suggest that Nfasc may be required for rod connectivity and Nrcam for cone connectivity.
Conclusions :
Our findings support a novel role for Nfasc and Nrcam in photoreceptor connectivity. Future work will further disseminate these molecular interactions to reveal new molecular pathways that guide selective wiring of photoreceptors. Through these experiments, we will uncover the molecular mechanisms involved in complex wiring of neural circuits during development.
This is a 2021 ARVO Annual Meeting abstract.