Genetic access to neurons in the accessory optic system reveals a role for Sema6A in midbrain circuitry mediating motion perception

Abstract

The accessory optic system (AOS) detects retinal image slip and reports it to the oculomotor system for reflexive image stabilization. Here, we characterize two Cre lines that permit genetic access to AOS circuits responding to vertical motion. The first (Pcdh9-Cre) labels only one of the four subtypes of ON direction-selective retinal ganglion cells (ON-DS RGCs), those preferring ventral retinal motion. Their axons diverge from the optic tract just behind the chiasm and selectively innervate the medial terminal nucleus (MTN) of the AOS. Unlike most RGC subtypes examined, they survive after optic nerve crush. The second Cre-driver line (Pdzk1ip1-Cre) labels postsynaptic neurons in the MTN. These project predominantly to the other major terminal nucleus of the AOS, the nucleus of the optic tract (NOT). We find that the transmembrane protein semaphorin 6A (Sema6A) is required for the formation of axonal projections from the MTN to the NOT, just as it is for the retinal innervation of the MTN. These new tools permit manipulation of specific circuits in the AOS and show that Sema6A is required for establishing AOS connections in multiple locations.

Transplantation of miPSC/mESC-derived retinal ganglion cells into healthy and glaucomatous retinas

“…Another compelling example for this enrichment is the semaphorin-plexin pathway ( Figure S4 C), which is known to be essential for axon guidance along the visual pathway during development. 24 , 25 , 26 Furthermore, when comparing intrinsic host RGCs and donor RGCs at 1 week post-transplant to newly transplanted day 1 donor RGCs ( Figure S5 A), it is apparent how pathways involved in synaptic plasticity and transmission only become enriched after the initial survival phase and within 1 week of transplant closely match the host. When analyzing whole mounts this observation is matched, as most non-integrated donor cells are cleared or die off within the first week post-transplant, arguing that only donor cells that establish cell-surface signaling or synaptic contact with the host tissue can survive and ultimately integrate.…”

Spatiotemporally Asymmetric Excitation Supports Mammalian Retinal Motion Sensitivity

“…To test a potential role of presynaptic mechanisms, we monitored released glutamate using two-photon imaging [10, 12, 29]. We targeted the dendrites of genetically labeled ON DS cells in Pcdh9-Cre mice [30, 31] (Figure S1B) with the glutamate indicator iGluSnFr delivered by adeno-associated virus (AAV) (Figure 2). To estimate the temporal filtering property in the glutamate releases, we used a static flash stimulus that temporally modulates temporal frequency and contrast (“modulating flash”) [29, 32].…”

“…Wild-type mice (C57BL/6J) were obtained from Janvier labs. Hoxd10-EGFP [27] and Pcdh9-Cre [30, 31] mice were obtained from Mutant Mouse Research and Resource Centers (strains: STOCK Tg(Hoxd10-EGFP)LT174Gsat/Mmucd and STOCK Tg(Pcdh-9-cre)NP276Gsat/Mmucd) and backcrossed to C57BL/6J mice for more than 5 generations. We used 4- to 16-week-old mice of either sex.…”

Intra-striatal AAV2.retro administration leads to extensive retrograde transport in the rhesus macaque brain: implications for disease modeling and therapeutic development

“…Mixed libraries of AAV cap variants were injected into discreet regions of the mouse CNS and variants were selected if they efficiently transported to neuronal cell bodies sending long-range projections to the site of AAV injection 31 . Since its creation, AAV2.retro has been used in mouse and rat models to target a multitude of CNS pathways including the amygdala via the ventral medial hypothalamus 32 , the thalamus via the anterior cingulate cortex 33 , the claustrum via the prefrontal cortex 34 , and more [35][36][37] . Taken together, these studies demonstrate that AAV2.retro is a powerful molecular tool capable of robust retrograde transport enabling the manipulation of neuronal pathways and circuits.…”