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Review
. 2014 Oct;37(10):594-603.
doi: 10.1016/j.tins.2014.07.009. Epub 2014 Aug 21.

Neuronal remodeling in retinal circuit assembly, disassembly, and reassembly

Florence D D'Orazi  1 , Sachihiro C Suzuki  1 , Rachel O Wong  2
Affiliations
Review

Neuronal remodeling in retinal circuit assembly, disassembly, and reassembly

Florence D D'Orazi et al. Trends Neurosci. 2014 Oct.

Abstract

Developing neuronal circuits often undergo a period of refinement to eliminate aberrant synaptic connections. Inappropriate connections can also form among surviving neurons during neuronal degeneration. The laminar organization of the vertebrate retina enables synaptic reorganization to be readily identified. Synaptic rearrangements are shown to help sculpt developing retinal circuits, although the mechanisms involved remain debated. Structural changes in retinal diseases can also lead to functional rewiring. This poses a major challenge to retinal repair because it may be necessary to untangle the miswired connections before reconnecting with proper synaptic partners. Here, we review our current understanding of the mechanisms that underlie circuit remodeling during retinal development, and discuss how alterations in connectivity during damage could impede circuit repair.

Keywords: circuit refinement; retina; retinal degeneration; synapses.

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Figures

Figure 1
Figure 1. Organization of retinal structure, connectivity and synapses
(A) Cross-section of the adult mouse retina (cover image from [7]). Cone photoreceptors (purple), horizontal cells (orange), bipolar cells (green), amacrine cells and retinal ganglion cells are labeled (red). Outer nuclear layer (ONL); inner nuclear layer (INL); retinal ganglion cell layer (GCL). Outer plexiform layer (OPL); inner plexiform layer (IPL). (B) Schematic showing major retinal pathways. Rod and cone photoreceptors detect changes in illumination, with rods functioning at low light levels, and cones at high light levels. Photoreceptor signals are conveyed by bipolar cells to retinal ganglion cells (RGCs). Cone bipolar cells (CBC) that largely contact cone photoreceptors are grouped into two major subclasses. Light increments depolarize ON-bipolar cells and hyperpolarize OFF-bipolar cells. ON and OFF synaptic connections are organized into separate laminae within the IPL. Horizontal cells (HC) and amacrine cells (AC) modulate information flow in the outer and inner retina, respectively. Rod bipolar cells (RBCs) predominantly convey rod input, and contact AII amacrine cells (AII AC) that inhibit transmission from OFF-CBCs. (C) Subcellular organization of retinal synapses. Schematic of a cone photoreceptor ribbon synapse (left). ON-CBCs and HCs invaginate the cone pedicle at sites apposed to a ribbon structure with tethered synaptic vesicles. OFF-CBCs make basal contacts with the cone pedicle [104]. mGluR6, metabotropic glutamate receptors on ON BCs; iGluR, ionotropic glutamate receptor on OFF-CBCs. Electron micrograph of a zebrafish cone pedicle at 5 days post-fertilization (right, from Yoshimatsu et al. [20]). HC and CBC processes are pseudocolored as in the schematic. (D) Schematic (left) and ultrastructure (right) of synapses in the IPL of an adult mouse retina. Shown here are BC and AC synapses. A ribbon synapse (small arrow) between a CBC and an RGC is apparent. The AC here provides feed-forward (FF, asterisk) inhibition onto the RGC and feedback (FB, large arrow) inhibition onto the BC on the right. Micrograph provided by A. Bleckert [105].
Figure 2
Figure 2. Strategies effecting RGC dendritic lamination and synaptic partner choice
At least four cellular strategies are employed to generate dendritic lamination patterns of RGCs and their connectivity. Distinct RGC types engage dendritic pruning to different extents (1,2,3) to achieve their final stratification pattern. Addition of arbors (4), instead of pruning, also occurs. Retinal ganglion cell, RGC; cone bipolar cells, C; rod bipolar cells, R. Orange, ON bipolar cell; Blue, OFF bipolar cell; Gray, rod bipolar cell.
Figure 3
Figure 3. Remodeling and perturbations to retinal excitatory synapses
(A) Mouse mutants in which ribbon arrangements are altered in cone photoreceptor terminals. Bassoon, cytomatrix protein [39, 40]; Cacna1f, voltage-gated calcium channel [41, 43]; Pikachurin, dystroglycan ligand [47]; WT, wildtype. (B) Morphological defects in rod photoreceptor terminals. nob2, partial loss-of-function mutation in cacna1f [42, 106], nob4, point mutation in mGluR6 [79]; NGL-2, netrin-G ligand 2 [82], Sema6, semaphorin 6A; PlexA4, Plexin A4 [81], Gnb3, G-protein beta subunit 3 [107].
Figure 4
Figure 4. Structural and functional rewiring in disease
(A) In healthy retina, rod bipolar cells (RBCs) synapse primarily with rod photoreceptors, localizing mGluR6 to invaginating dendritic tips apposed to synaptic ribbons. (Left) Sprouting of RBC dendrites into the ONL in rod transmission-defective mutants [43,73]. (Right) Rod degeneration in the rd10 model of Retinitis Pigmentosa (RP) leads to retraction of RBC dendrites [, –58], and a simultaneous loss or redistribution of mGluR6 to the cell body and axon [56, 57]. RBC dendritic retraction may precede the formation of synapses with novel partners, such as cone photoreceptors [54, 56, 58]. (B) Changes in receptor localization and expression at synaptic contacts between bipolar cells and cone photoreceptors in disease models (rd1 and rd10) [–58, 82] and in human RP[–85].
Figure I
Figure I. Phenotypes of mouse mutants with synapse lamination defects
In wild type retina (WT), neurites of tyrosine hydroxylase-expressing amacrine cells (TH) arborize in the OFF sublamina of the IPL, where they make synapses with the dendrites of M1 type melanopsin-expressing retinal ganglion cells (M1 RGC). AII amacrine cells (AII) and rod bipolar cells (RBC) form synaptic contacts in the inner tier of the ON sublamina. In Sema5A/5B double mutant mice (Sema5A/5B dKO), neurites of TH expressing amacrine cells and AII amacrine cells arborize erroneously in the inner nuclear layer (INL). The dendrites of M1 RGCs also extend into the INL and associate with TH positive neurites. In the Sema6A mutant (Sema6A KO), TH amacrine cells processes invade the ON sublamina, where they associate with aberrant M1 RGC dendrites. Horizontal cell axons also overshoot into the outer nuclear layer (ONL). It remains to be seen whether AII amacrine cells are affected in the Sema6A mutant. In the Fat3 mutant (Fat3 KO), TH amacrine cells project extra processes toward the outer misplaced plexiform layer (OMPL) in the INL. AII amacrine cells send extra neurites to the OMPL and the OPL. Although to date there is no data to show whether there is an effect on M1 RGCs, synaptic coupling between AII amacrine cells and rod bipolar cells is maintained but mislocalized to the inner misplaced plexiform layer (IMPL) beneath the retinal ganglion cell layer (GCL).
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