Shedding light on class-specific wiring: development of intrinsically photosensitive retinal ganglion cell circuitry

Abstract

Neural circuits associated with retinal ganglion cells have long been used as models for investigating the mechanisms that govern circuit development and function. Similar to neurons in the brain, retinal ganglion cells are subdivided into distinct classes based upon their morphology, physiology, and patterns of connectivity. Newly developed transgenic tools in which individual classes of retinal ganglion cells are labeled with reporter proteins have recently provided a method to study the development of their class-specific circuitry. Here, we examine a single class of intrinsically photosensitive retinal ganglion cells and discuss their class-specific circuitry, as well as the cellular and molecular mechanisms that govern assembly of this circuitry.

Figure 1

Basic wiring of the retina. The vertebrate retina contains five main cell types – photoreceptors (rods [R] and cones [C]), three types of interneurons (horizontal cells [H], amacrine cells [A], and bipolar cells [B]) and projection neurons (retinal ganglion cells [RGCs]). These cells are arranged in three distinct cell layers within the retina, the outer nuclear layer (ONL) which contains rod and cone photoreceptors, the inner nuclear layer (INL) which contains the three types of interneurons, and the ganglion cell layer (GCL) which contains both RGCs and displaced amacrine cells (dA). Synaptic connections between retinal neurons are confined to 2 synaptic layers – the outer plexiform layer (OPL) and inner plexiform layer (IPL). Black dashed line indicates the division of the inner plexiform layer into ON and OFF divisions of the IPL. Yellow arrows highlight the path of light through the retina. IPL(off) – OFF division of the inner plexiform layer; IPL(on) – ON division of the inner plexiform layer; S1-5 – sublaminae of the inner plexiform layer.

Figure 2

Morphological differences between classes of ipRGCs. Stratification of the dendrites of each of the 5 classes of ipRGC (and displaced M1 ipRGCs [dM1]) are depicted in retinal cross-sections. Insets show the morphology of dendritic arborizations for each class as seen in retinal whole-mount preparations. Black dashed line indicates the division of the inner plexiform layer into ON and OFF divisions of the IPL. ONL – outer nuclear layer; OPL – outer plexiform layer; INL – inner nuclear layer, IPL(off) – OFF division of the inner plexiform layer; IPL(on) – ON division of the inner plexiform layer; GCL– ganglion cell layer.

Figure 3

Development of intraretinal circuitry of M1 ipRGCs. A. Schematic diagram summarizes the synaptic inputs onto M1 ipRGC (M1) dendrites by Off-bipolar cells (Off), On-bipolar cells (On), rod-bipolar cells (Rb), dopaminergic amacrine cells (D) and inhibitory amacrine cells (A). Rod bipolar cells also exert influence on M1 ipRGC activity indirectly through AII amacrine cell-On bipolar cell circuitry. Gap junction (gj) coupling of M1 ipRGCs and displaced amacrine cells (dA) within the ganglion cell layer (GCL) is depicted with a purple dashed line. *** highlights reciprocal connections between dopaminergic amacrine cell and M1 ipRGCs dendrites, which allow M1 ipRGCs to exert influence over neurons in the INL. ‘+’ and ‘−’ denote whether excitatory or inhibitory receptors are present at synaptic sites. B. Distribution of PlexinA4 (blue) and Sema6A (red) in mouse retina. C. Genetic removal of PlexinA4 (PlexinA4^−/−) or Sema6A (Sema6A^−/−) leads to the mistargeting of dopaminergic amacrine cell (D) and M1 ipRGC (M) dendrites into the ON division of the inner plexiform layer (arrows). R- rod photoreceptor; C – cone photoreceptor; AII – AII amacrine cell; S1-5 – sublaminae of the inner plexiform layer; ONL – outer nuclear layer; OPL – outer plexiform layer; INL – inner nuclear layer, IPL(off) – OFF division of the inner plexiform layer; IPL(on) – ON division of the inner plexiform layer.

Figure 4

Development of central projections of M1 ipRGCs, A. 5 nuclei (red) receive dense projections from M1 ipRGCs (green): suprachiasmatic nucleus (SCN), ventral lateral geniculate nucleus (vLGN); intergeniculate nucleus (IGL), lateral habenula (LH) and the olivary pretectal nucleus (OPN). ‘b’ denotes those nuclei that receive binocular input from M1 ipRGCs. ‘*’ denotes that only the outer ‘shell’ of the OPN is innervated by M1 ipRGCs. B. Development of M1 ipRGC innervation to the SCN, lateral geniculate nucleus (LGN, which is composed of the vLGN, IGL and dorsal LGN [dLGN]), and OPN at postnatal day 0,3 and 7 (P0, P3, P7 respectively) in mice. vLGN and IGL are innervated by M1 ipRGCs by P0, while SCN is innervated by P3 (although only the contralateral SCN is innervated by M1 ipRGC axons at this early age), and the ‘shell’ of the OPN is innervated by P7. C. Reelin (blue) is expressed in the ventral lateral geniculate nucleus (vLGN) and intergeniculate nucleus (IGL). M1 ipRGCs (M1) express disabled-1 (Dab1; red), an intracellular component of the reelin signaling pathway. D. M1 ipRGC axons are mistargeted in spontaneously generated mouse mutants lacking either Reelin (reln^rl/rl) or Dab1 (dab1^scm/scm).