The retinal fovea in human and nonhuman primates is essential for high acuity and color vision. Within the fovea lies specialized circuitry in which signals from a single cone photoreceptor are largely conveyed to one ON and one OFF type midget bipolar cell (MBC), which in turn connect to a single ON or OFF midget ganglion cell (MGC), respectively. Restoring foveal vision requires not only photoreceptor replacement but also appropriate reconnection with surviving ON and OFF MBCs and MGCs. However, our current understanding of the effects of cone loss on the remaining foveal midget pathway is limited. We thus used serial block-face electron microscopy to determine the degree of plasticity and potential remodeling of this pathway in adult Macaca fascicularis several months after acute photoreceptor loss upon photocoagulation. We reconstructed MBC structure and connectivity within and adjacent to the region of cone loss. We found that MBC dendrites within the scotoma retracted and failed to reach surviving cones to form new connections. However, both surviving cones and ON and OFF MBC dendrites at the scotoma border exhibited remodeling, suggesting that these neurons can demonstrate plasticity and rewiring at maturity. At six months postlesion, disconnected OFF MBCs clearly lost output ribbon synapses with their postsynaptic partners, whereas the majority of ON MBCs maintained their axonal ribbon numbers, suggesting differential timing or extent in ON and OFF midget circuit remodeling after cone loss. Our findings raise rewiring considerations for cell replacement approaches in the restoration of foveal vision.

The neural pathways that start human color vision begin in the complex synaptic network of the foveal retina where signals originating in long (L), middle (M), and short (S) wavelength-sensitive cone photoreceptor types are compared through antagonistic interactions, referred to as opponency. In nonhuman primates, two cone opponent pathways are well established: an L vs. M cone circuit linked to the midget ganglion cell type, often called the red-green pathway, and an S vs. L + M cone circuit linked to the small bistratified ganglion cell type, often called the blue-yellow pathway. These pathways have been taken to correspond in human vision to cardinal directions in a trichromatic color space, providing the parallel inputs to higher-level color processing. Yet linking cone opponency in the nonhuman primate retina to color mechanisms in human vision has proven particularly difficult. Here, we apply connectomic reconstruction to the human foveal retina to trace parallel excitatory synaptic outputs from the S-ON (or \"blue-cone\") bipolar cell to the small bistratified cell and two additional ganglion cell types: a large bistratified ganglion cell and a subpopulation of ON-midget ganglion cells, whose synaptic connections suggest a significant and unique role in color vision. These two ganglion cell types are postsynaptic to both S-ON and L vs. M opponent midget bipolar cells and thus define excitatory pathways in the foveal retina that merge the cardinal red-green and blue-yellow circuits, with the potential for trichromatic cone opponency at the first stage of human vision.

In most avian retinas, double cones (consisting of a principal and accessory member) outnumber other photoreceptor types and have been associated with various functions, such as encoding luminance, sensing polarized light, and magnetoreception. However, their down-stream circuitry is poorly understood, particularly across bird species. Analysing species differences is important to understand changes in circuitry driven by ecological adaptations. We compare the ultrastructure of double cones and their postsynaptic bipolar cells between a night-migratory European robin and non-migratory chicken. We discover four previously unidentified bipolar cell types in the European robin retina, including midget-like bipolar cells mainly connected to one principal member. A downstream ganglion cell reveals a complete midget-like circuit similar to a circuit in the peripheral primate retina. Additionally, we identify a selective circuit transmitting information from a specific subset of accessory members. Our data highlight species-specific differences in double cone to bipolar cell connectivity, potentially reflecting ecological adaptations.

In the central nervous system of vertebrates, glutamate serves as the primary excitatory neurotransmitter. However, in the retina, glutamate released from photoreceptors causes hyperpolarization in post-synaptic ON-bipolar cells through a glutamate-gated chloride current, which seems paradoxical. Our research reveals that this current is modulated by two excitatory glutamate transporters, EAAT5b and EAAT7. In the zebrafish retina, these transporters are located at the dendritic tips of ON-bipolar cells and interact with all four types of cone photoreceptors. The absence of these transporters leads to a decrease in ON-bipolar cell responses, with eaat5b mutants being less severely affected than eaat5b/eaat7 double mutants, which also exhibit altered response kinetics. Biophysical investigations establish that EAAT7 is an active glutamate transporter with a predominant anion conductance. Our study is the first to demonstrate the direct involvement of post-synaptic glutamate transporters in inhibitory direct synaptic transmission at a central nervous system synapse.

In retinitis pigmentosa (RP), rod and cone photoreceptors degenerate, depriving downstream neurons of light-sensitive input, leading to vision impairment or blindness. Although downstream neurons survive, some undergo morphological and physiological remodeling. Bipolar cells (BCs) link photoreceptors, which sense light, to retinal ganglion cells (RGCs), which send information to the brain. While photoreceptor loss disrupts input synapses to BCs, whether BC output synapses remodel has remained unknown. Here we report that synaptic output from BCs plummets in RP mouse models of both sexes owing to loss of voltage-gated Ca2+ channels. Remodeling reduces the reliability of synaptic output to repeated optogenetic stimuli, causing RGC firing to fail at high-stimulus frequencies. Fortunately, functional remodeling of BCs can be reversed by inhibiting the retinoic acid receptor (RAR). RAR inhibitors targeted to BCs present a new therapeutic opportunity for mitigating detrimental effects of remodeling on signals initiated either by surviving photoreceptors or by vision-restoring tools.

Age-related neuronal adaptations are known to help maintain function. This study aims to examine gross age-related in vivo retinal functional adaptations (using electroretinography) in young and middle aged C57BL/6J and Thy1-YFPh mice and to relate this to in vivo retinal structure (using optical coherence tomography). Electroretinography responses were generally larger in Thy1-YFPh mice than in C57BL/6J mice, with similar in vivo retinal layer thicknesses except for longer inner/outer photoreceptor segment in Thy1-YFPh mice. Relative to 3-month-old mice, 12-month-old mice showed reduced photoreceptor (C57BL/6J 84.0±2.5 %; Thy1-YFPh 80.2±5.2 %) and bipolar cell (C57BL/6J 75.6±2.3 %; Thy1-YFPh 68.1±5.5 %) function. There was relative preservation of ganglion cell function (C57BL/6J 79.7±3.7 %; Thy1-YFPh 91.7±5.0 %) with age, which was associated with increased b-wave (bipolar cell) sensitivities to light. Ganglion cell function was correlated with both b-wave amplitude and sensitivity. This study shows that there are normal age-related adaptations to preserve functional output. Different mouse strains may have varied age-related adaptation capacity and should be taken into consideration when examining age-related susceptibility to injury.

Retinal prosthetics are one of the leading therapeutic strategies to restore lost vision in patients with retinitis pigmentosa and age-related macular degeneration. Much work has described patterns of spiking in retinal ganglion cells (RGCs) in response to electrical stimulation, but less work has examined the underlying retinal circuitry that is activated by electrical stimulation to drive these responses. Surprisingly, little is known about the role of inhibition in generating electrical responses or how inhibition might be altered during degeneration. Using whole-cell voltage-clamp recordings during subretinal electrical stimulation in the rd10 and wild-type (wt) retina, we found electrically evoked synaptic inputs differed between ON and OFF RGC populations, with ON cells receiving mostly excitation and OFF cells receiving mostly inhibition and very little excitation. We found that the inhibition of OFF bipolar cells limits excitation in OFF RGCs, and a majority of both pre- and postsynaptic inhibition in the OFF pathway arises from glycinergic amacrine cells, and the stimulation of the ON pathway contributes to inhibitory inputs to the RGC. We also show that this presynaptic inhibition in the OFF pathway is greater in the rd10 retina, compared with that in the wt retina.

β-synuclein, a member of the synuclein family, is frequently co-expressed with α-synuclein in the neural system, where it serves to inhibit abnormal aggregation of α-synuclein in neurodegenerative diseases. Beyond its role in pathological conditions, β-synuclein plays various functions independently of α-synuclein. In our investigation, we discovered a broader expression of β-synuclein in the mouse retina compared to α-synuclein. This widespread pattern implies its potential significance in the retina. Through detailed examination via light- and electron-microscopic immunocytochemistry, we identified β-synuclein expression from the inner segment (IS) and outer segment (OS) of photoreceptor cells to the ganglion cell layer (GCL). Our findings unveiled unique features, including β-synuclein immunoreactive IS and OS of cones, higher expression in cone pedicles than in rod spherules, absence in horizontal cells, limited expression in cone bipolar dendrites and somas, higher expression in cone bipolar terminals, presence in most amacrine cells, and expression in almost majority of somas in GCL with an absence in intrinsically photosensitive retinal ganglion cell (ipRGCs) processes. Notably, all cholinergic amacrine cells express high β- but not α-synuclein, while dopaminergic amacrine cells express α-synuclein exclusively. These distinctive expression patterns offer valuable insights for further exploration into the functions of β-synuclein and its potential role in synuclein pathology within the retina.

In the pupillary light response (PLR), increases in ambient light constrict the pupil to dampen increases in retinal illuminance. Here, we report that the pupillary reflex arc implements a second input-output transformation; it senses temporal contrast to enhance spatial contrast in the retinal image and increase visual acuity. The pupillary contrast response (PCoR) is driven by rod photoreceptors via type 6 bipolar cells and M1 ganglion cells. Temporal contrast is transformed into sustained pupil constriction by the M1\'s conversion of excitatory input into spike output. Computational modeling explains how the PCoR shapes retinal images. Pupil constriction improves acuity in gaze stabilization and predation in mice. Humans exhibit a PCoR with similar tuning properties to mice, which interacts with eye movements to optimize the statistics of the visual input for retinal encoding. Thus, we uncover a conserved component of active vision, its cell-type-specific pathway, computational mechanisms, and optical and behavioral significance.

We consider a model of basic inner retinal connectivity where bipolar and amacrine cells interconnect and both cell types project onto ganglion cells, modulating their response output to the brain visual areas. We derive an analytical formula for the spatiotemporal response of retinal ganglion cells to stimuli, taking into account the effects of amacrine cells inhibition. This analysis reveals two important functional parameters of the network: (1) the intensity of the interactions between bipolar and amacrine cells and (2) the characteristic timescale of these responses. Both parameters have a profound combined impact on the spatiotemporal features of retinal ganglion cells\' responses to light. The validity of the model is confirmed by faithfully reproducing pharmacogenetic experimental results obtained by stimulating excitatory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) expressed on ganglion cells and amacrine cells\' subclasses, thereby modifying the inner retinal network activity to visual stimuli in a complex, entangled manner. Our mathematical model allows us to explore and decipher these complex effects in a manner that would not be feasible experimentally and provides novel insights in retinal dynamics.