Postsynaptic NMDA Receptor Expression Is Required for Visual Corticocollicular Projection Refinement in the Mouse Superior Colliculus.

Efficient sensory processing of spatial information is facilitated through the organization of neuronal connections into topographic maps of space. In integrative sensory centers, converging topographic maps must be aligned to merge spatially congruent information. The superior colliculus (SC) receives topographically ordered visual inputs from retinal ganglion cells (RGCs) in the eye and layer 5 neurons in the primary visual cortex (L5-V1). Previous studies suggest that RGCs instruct the alignment of later-arriving L5-V1 inputs in an activity-dependent manner. However, the molecular mechanisms underlying this remain unclear. Here, we explored the role of NMDA receptors in visual map alignment in the SC using a conditional genetic knockout approach. We leveraged a novel knock-in mouse line that expresses tamoxifen-inducible Cre recombinase under the control of the Tal1 gene (Tal1CreERT2 ), which we show allows for specific recombination in the superficial layers of the SC. We used Tal1CreERT2 mice of either sex to conditionally delete the obligate GluN1 subunit of the NMDA receptor (SC-cKO) during the period of visual map alignment. We observed a significant disruption of L5-V1 axon terminal organization in the SC of SC-cKO mice. Importantly, retinocollicular topography was unaffected in this context, suggesting that alignment is also disrupted. Time-course experiments suggest that NMDA receptors may play a critical role in the refinement of L5-V1 inputs in the SC. Together, these data implicate NMDA receptors as critical mediators of activity-dependent visual map alignment in the SC.SIGNIFICANCE STATEMENT Alignment of topographic inputs is critical for integration of spatially congruent sensory information; however, little is known about the mechanisms underlying this complex process. Here, we took a conditional genetic approach to explore the role of NMDA receptors in the alignment of retinal and cortical visual inputs in the superior colliculus. We characterize a novel mouse line providing spatial and temporal control of recombination in the superior colliculus and reveal a critical role for NMDA expression in visual map alignment. These data support a role for neuronal activity in visual map alignment and provide mechanistic insight into this complex developmental process.

NMDA Receptor Expression by Retinal Ganglion Cells Is Not Required for Retinofugal Map Formation nor Eye-Specific Segregation in the Mouse.

Retinal ganglion cells (RGCs) project topographically to the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). Spontaneous activity plays a critical role in retinotopic mapping in both regions; however, the molecular mechanisms underlying activity-dependent refinement remain unclear. Previous pharmacologic studies implicate NMDA receptors (NMDARs) in the establishment of retinotopy. In other brain regions, NMDARs are expressed on both the presynaptic and postsynaptic side of the synapse, and recent work suggests that presynaptic and postsynaptic NMDARs play distinct roles in retinotectal developmental dynamics. To directly test the role of NMDARs expressed by RGCs in retinofugal map formation, we took a conditional genetic knock-out approach to delete the obligate GluN1 subunit of NMDARs in RGCs. Here, we demonstrate reduced GluN1 expression in the retina of Chrnb3-Cre;GluN1flox/flox (pre-cKO) mice without altered expression in the SC. Anatomical tracing experiments revealed no significant changes in termination zone size in the SC and dLGN of pre-cKO mice, suggesting NMDAR function in RGCs is not an absolute requirement for topographic refinement. Further, we observed no change in the eye-specific organization of retinal inputs to the SC nor dLGN. To verify that NMDA induces activity in RGC terminals, we restricted GCaMP5 expression to RGCs and confirmed induction of calcium transients in RGC terminals. Together, these findings demonstrate that NMDARs expressed by RGCs are not required for retinofugal topographic map formation nor eye-specific segregation in the mouse.

Wiring subcortical image-forming centers: Topography, laminar targeting, and map alignment.

Efficient sensory processing is a complex and important function for species survival. As such, sensory circuits are highly organized to facilitate rapid detection of salient stimuli and initiate motor responses. For decades, the retina's projections to image-forming centers have served as useful models to elucidate the mechanisms by which such exquisite circuitry is wired. In this chapter, we review the roles of molecular cues, neuronal activity, and axon-axon competition in the development of topographically ordered retinal ganglion cell (RGC) projections to the superior colliculus (SC) and dorsal lateral geniculate nucleus (dLGN). Further, we discuss our current state of understanding regarding the laminar-specific targeting of subclasses of RGCs in the SC and its homolog, the optic tectum (OT). Finally, we cover recent studies examining the alignment of projections from primary visual cortex with RGCs that monitor the same region of space in the SC.