Development of the vertebrate retinal direction-selective circuit

Abstract

The vertebrate retina contains an array of neural circuits that detect distinct features in visual space. Direction-selective (DS) circuits are an evolutionarily conserved retinal circuit motif - from zebrafish to rodents to primates - specialized for motion detection. During retinal development, neuronal subtypes that wire DS circuits form exquisitely precise connections with each other to shape the output of retinal ganglion cells tuned for specific speeds and directions of motion. In this review, we follow the chronology of DS circuit development in the vertebrate retina, including the cellular, molecular, and activity-dependent mechanisms that regulate the formation of DS circuits, from cell birth and migration to synapse formation and refinement. We highlight recent findings that identify genetic programs critical for specifying neuronal subtypes within DS circuits and molecular interactions essential for responses along the cardinal axes of motion. Finally, we discuss the roles of DS circuits in visual behavior and in certain human visual disease conditions. As one of the best-characterized circuits in the vertebrate retina, DS circuits represent an ideal model system for studying the development of neural connectivity at the level of individual genes, cells, and behavior.

Keywords: Circuit; Direction selectivity; Retina; Visual system.

Fig. 1.. Cell types of the retina.

Cell bodies of the retina are organized into three layers: the outer nuclear layer (ONL), containing rod and cone photoreceptors; the inner nuclear layer (INL), containing horizontal cells (HCs), bipolar cells (BCs), which are divided into ON and OFF subtypes, and amacrine cells (ACs); and the ganglion cell layer (GCL), containing retinal ganglion cells (RGCs) and displaced ACs. Synapses between OPL-residing and INL-residing cells form within the outer plexiform layer (OPL), while synapses between INL-residing and GCL-residing cells form within the inner plexiform layer (IPL). RGCs depicted include direction-selective ganglion cells (DSGCs) which are categorized as responsive to light onset (ON DSGCs) or both light onset and offset (ON-OFF DSGCs). ACs depicted are starburst amacrine cells (SACs), which provide asymmetric inhibition onto DSGCs; SACs responding to light onset (ON SACs) reside in the GCL, while SACs responding to light offset (OFF SACs) reside in the INL. Specific subtypes of OFF and ON BCs wire in direction-selective circuits, including OFF BC2s/BC3as and ON BC5s/BC7s.

Fig. 2.. Developmental time course of ON/ON-OFF DS circuit components and effects of key LOF mutants.

(A) Cross-section view of the developing retina, E11-P21. E11-E16.5: After birth, SACs migrate to their appropriate laminar positions, with OFF SACs ultimately settling in the outer neuroblastic layer (ONBL) while ON SACs migrate into the inner neuroblastic layer (INBL). E17.5-P3: SACs refine their dendritc arbors to organize the ON and OFF DS sublaminae of the IPL. P4-P21: DSGCs organize dendrites into discrete ON and OFF laminae; SACs form asymmetric inhibitory connections onto DSGCs. (B) En face view of developing SACs, P3-P12; SAC dendrites develop self-avoidance over time. (C) Pcdhγ LOF impairs SAC dendritic self-avoidance. (D) Fezf1 LOF causes all SACs to settle in the INL and become OFF SACs. (E) Megf10 LOF reduces the regularity of the mosaic spacing of SAC somas. (F) LOF of Sema6a and/or Plxna2 causes the dendrites of OFF and ON SACs to form crossovers across DS sublaminae. (G) Cdh8 LOF induces OFF BC2s to terminate in the ON sublamina, while Cdh9 induces ON BC5s to terminate in the OFF sublamina. Dashed lines in (G) denote original laminar positions.

Fig. 3.. Selective role for Frmd7 in development of horizontal DS circuitry.

(A) Mice with Frmd7 LOF exhibit a loss of horizontal, but not vertical, OKR. Shown are eye tracking movements (ETMs) in response to slow motion stimuli in the indicated directions (yellow, purple, green, and blue arrows). (B) ON DSGCs tuned to prefer horizontal motion respond equally strongly to all directional stimuli following Frmd7 LOF, whereas those tuned to prefer vertical motion are unaffected. (C) SAC morphology is normal in Frmd7 mutants. (D) FRMD7 protein is distributed symmetrically across the SAC dendritic arbor between P3 and P7. (E) Two Frmd7 mutations identified in congenital nystagmus patients impair the ability of FRMD7 to associate with GABRA2, a component of inhibitory neurotransmitter receptors. D = dorsal; N = nasal; V = ventral; T.= temporal.