Neurexin 3 is required for the specific S-cone to S-cone bipolar cell synapse in the mammalian retina

Specific wiring is essential for sensory systems to precisely relay information to higher brain regions. The retina, an approachable part of the brain, is an ideal model for studying neural circuits due to its well-organized structure. In the retina, S-cone photoreceptors sense and relay short-wavelength (e.g., blue) light signals for encoding color information and other environmental cues. S-cones usually account for less than 10% of cones and are precisely connected to S-cone bipolar cells (SCBCs). This connection is ancient and highly conserved across species, indicating essential functions. How this wiring specificity is formed and maintained, however, is not understood. To unveil the molecular mechanisms underlying this highly specific connection, we sequenced the transcriptomes of thirteen-lined ground squirrel (TLGS) photoreceptors. We chose TLGS for their cone-rich retina and the absence of cones that co-express multiple opsin proteins, as compared to mice. We used a targeted SMART-seq approach to obtain high-resolution transcriptomes from S- and M-cone photoreceptors and identified a cell-adhesion molecule, Nrxn3 , as a potential candidate mediating the S-cone to SCBC connection. Given the limitations of genetic manipulation in TLGS, we utilized mouse models to study the function of Nrxn3 in S-cones. In ‘true’ S-cones (S-opsin+/M-opsin-) that lack Nrxn3 expression, the number of connections with SCBCs was drastically reduced, indicating a critical role of Nrxn3 for this synapse. While neurexins are well known for their diverse roles in regulating various synapses, this study is the first to document its crucial role in mediating or maintaining a specific synapse in the central nervous system. In addition, the differentially expressed genes identified here provide a valuable resource for further investigating cone subtype-specific functions. ### Competing Interest Statement The authors have declared no competing interest.