Distinct roles for inhibition in spatial and temporal tuning of local edge detectors in the rabbit retina.

This paper examines the role of inhibition in generating the receptive-field properties of local edge detector (LED) ganglion cells in the rabbit retina. We confirm that the feed-forward inhibition is largely glycinergic but, contrary to a recent report, our data demonstrate that the glycinergic inhibition contributes to temporal tuning for the OFF and ON inputs to the LEDs by delaying the onset of spiking; this delay was more pronounced for the ON inputs (∼ 340 ms) than the OFF inputs (∼ 12 ms). Blocking glycinergic transmission reduced the delay to spike onset and increased the responses to flickering stimuli at high frequencies. Analysis of the synaptic conductances indicates that glycinergic amacrine cells affect temporal tuning through both postsynaptic inhibition of the LEDs and presynaptic modulation of the bipolar cells that drive the LEDs. The results also confirm that presynaptic GABAergic transmission contributes significantly to the concentric surround antagonism in LEDs; however, unlike presumed LEDs in the mouse retina, the surround is only partly generated by spiking amacrine cells

GABA_{B} Receptors Regulate Chick Retinal Calcium Waves

Correlated spiking activity and associated Ca²⁺ waves in the developing retina are important in determining the connectivity of the visual system. Here, we show that GABA, via GABA_{B} receptors, regulates the temporal characteristics of Ca²⁺ waves occurring before synapse formation in the embryonic chick retina. Blocking ionotropic GABA receptors did no affect these Ca²⁺ transients. However, when these receptors were blocked, GABA abolished the transients, as did the GABA_{B} agonist baclofen. The action of baclofen was prevented by the GABA_{B} antagonistp-3-aminopropyl-p-diethoxymethyl phosphoric acid (CGP35348). CGP35348 alone increased the duration of the transients, showing that GABA_{B} receptors are tonically activated by endogenous GABA. Blocking the GABA transporter GAT-1 with 1-(4,4-diphenyl-3-butenyl)-3-piperidine carboxylic acid (SKF89976A) reduced the frequency of the transients. This reduction was prevented by CGP35348 and thus resulted from activation of GABA_{B} receptors by an increase in external [GABA]. The effect of GABA_{B} receptor activation persisted in the presence of activators and blockers of the cAMP–PKA pathway. Immunocytochemistry showed GABA_{B} receptors and GAT-1 transporters on ganglion and amacrine cells from the earliest times when Ca²⁺ waves occur (embryonic day 8). Patch-clamp recordings showed that K⁺ channels on ganglion cell layer neurons are not modulated by GABA_{B} receptors, whereas Ca²⁺ channels are; however, Ca²⁺ channel blockade with ω-conotoxin-GVIA or nimodipine did not prevent Ca²⁺ waves. Thus, the regulation of Ca²⁺ waves by GABA_{B} receptors occurs independently of N- and L-type Ca²⁺ channels and does not involve K⁺ channels of the ganglion cell layer. GABA_{B} receptors are likely to be of key importance in regulating retinal development

Lack of the Sodium-Driven Chloride Bicarbonate Exchanger NCBE Impairs Visual Function in the Mouse Retina

Regulation of ion and pH homeostasis is essential for normal neuronal function. The sodium-driven chloride bicarbonate exchanger NCBE (Slc4a10), a member of the SLC4 family of bicarbonate transporters, uses the transmembrane gradient of sodium to drive cellular net uptake of bicarbonate and to extrude chloride, thereby modulating both intracellular pH (pHi) and chloride concentration ([Cl-]i) in neurons. Here we show that NCBE is strongly expressed in the retina. As GABAA receptors conduct both chloride and bicarbonate, we hypothesized that NCBE may be relevant for GABAergic transmission in the retina. Importantly, we found a differential expression of NCBE in bipolar cells: whereas NCBE was expressed on ON and OFF bipolar cell axon terminals, it only localized to dendrites of OFF bipolar cells. On these compartments, NCBE colocalized with the main neuronal chloride extruder KCC2, which renders GABA hyperpolarizing. NCBE was also expressed in starburst amacrine cells, but was absent from neurons known to depolarize in response to GABA, like horizontal cells. Mice lacking NCBE showed decreased visual acuity and contrast sensitivity in behavioral experiments and smaller b-wave amplitudes and longer latencies in electroretinograms. Ganglion cells from NCBE-deficient mice also showed altered temporal response properties. In summary, our data suggest that NCBE may serve to maintain intracellular chloride and bicarbonate concentration in retinal neurons. Consequently, lack of NCBE in the retina may result in changes in pHi regulation and chloride-dependent inhibition, leading to altered signal transmission and impaired visual function

Intraneuronal information processing, directional selectivity and memory for spatio-temporal sequences.

Interacting intracellular signalling pathways can perform computations on a scale that is slower, but more fine-grained, than the interactions between neurons upon which we normally build our computational models of the brain (Bray D 1995 Nature 376 307-12). What computations might these potentially powerful intraneuronal mechanisms be performing? The answer suggested here is: storage of spatio-temporal trajectories; thus, neurons have some of the capacities required to perform such a task. In the retina, it is suggested that calcium-induced calcium release (CICR) may provide the basis for directional selectivity. In the cortex, if activation mechanisms with different delays could be separately reinforced at individual synapses then each such Hebbian super-synapse would store a memory trace of the delay between pre- and post-synaptic activity, forming an ideal basis for the memory and response to phase sequences

Monoaminergic modulation of photoreception in ascidian:evidence for a proto-hypothalamo-retinal territory

Background : The retina of craniates/vertebrates has been proposed to derive from a photoreceptor prosencephalic territory in ancestral chordates, but the evolutionary origin of the different cell types making the retina is disputed. Except for photoreceptors, the existence of homologs of retinal cells remains uncertain outside vertebrates. Methods : The expression of genes expressed in the sensory vesicle of the ascidian Ciona intestinalis including those encoding components of the monoaminergic neurotransmission systems, was analyzed by in situ hybridization or in vivo transfection of the corresponding regulatory elements driving fluorescent reporters. Modulation of photic responses by monoamines was studied by electrophysiology combined with pharmacological treatments. Results : We show that many molecular characteristics of dopamine-synthesizing cells located in the vicinity of photoreceptors in the sensory vesicle of the ascidian Ciona intestinalis are similar to those of amacrine dopamine cells of the vertebrate retina. The ascidian dopamine cells share with vertebrate amacrine cells the expression of the key-transcription factor Ptf1a, as well as that of dopamine-synthesizing enzymes. Surprisingly, the ascidian dopamine cells accumulate serotonin via a functional serotonin transporter, as some amacrine cells also do. Moreover, dopamine cells located in the vicinity of the photoreceptors modulate the light-off induced swimming behavior of ascidian larvae by acting on alpha2-like receptors, instead of dopamine receptors, supporting a role in the modulation of the photic response. These cells are located in a territory of the ascidian sensory vesicle expressing genes found both in the retina and the hypothalamus of vertebrates (six3/6, Rx, meis, pax6, visual cycle proteins). Conclusion : We propose that the dopamine cells of the ascidian larva derive from an ancestral multifunctional cell population located in the periventricular, photoreceptive field of the anterior neural tube of chordates, which also gives rise to both anterior hypothalamus and the retina in craniates/vertebrates. It also shows that the existence of multiple cell types associated with photic responses predates the formation of the vertebrate retina

Neural Coding of Green Flash in Retinal Bipolar Pathways

What visual information do the graded potentials among retinal bipolar pathways actually transmit from photoreceptors to ganglion cells? The answer does not exist. Even the graded electric signals have not been understood completely. Here, this paper tries to analyze the encoding mechanisms of graded signals among the parallel bipolar pathways in response to brief green flash. The typical ON, OFF and ON-OFF bipolar cells simultaneously abstracted vectors from green flash stimulus with sine-like functions on their dendritic plane. Atypical bipolar cell had the synchronously monopolar response in contrast to the bipolar responses of typical bipolar cells, they also annotated green flash with facilitated stochastic (asynchronous and rate-coded) responses. Some complex ON-OFF bipolar cells with large voltage-gated Na+ current could generate high-frequent asynchronous responses, others had synchronous ON-OFF responses to green flash. The green flash was synchronously and asynchronously represented by the multiple-dimension signaling space among the parallel bipolar pathways. These results unraveled the multiple-dimension neural codes for brief green flash, demonstrated the superior encoding capability of parallel bipolar pathways, and suggested the electrophysiological mechanisms of vision such as color space

General features of the retinal connectome determine the computation of motion anticipation

Motion anticipation allows the visual system to compensate for the slow speed of phototransduction so that a moving object can be accurately located. This correction is already present in the signal that ganglion cells send from the retina but the biophysical mechanisms underlying this computation are not known. Here we demonstrate that motion anticipation is computed autonomously within the dendritic tree of each ganglion cell and relies on feedforward inhibition. The passive and non-linear interaction of excitatory and inhibitory synapses enables the somatic voltage to encode the actual position of a moving object instead of its delayed representation. General rather than specific features of the retinal connectome govern this computation: an excess of inhibitory inputs over excitatory, with both being randomly distributed, allows tracking of all directions of motion, while the average distance between inputs determines the object velocities that can be compensated for

Decellularised extracellular matrix-derived peptides from neural retina and retinal pigment epithelium enhance the expression of synaptic markers and light responsiveness of human pluripotent stem cell derived retinal organoids

Tissue specific extracellular matrices (ECM) provide structural support and enable access to molecular signals and metabolites, which are essential for directing stem cell renewal and differentiation. To mimic this phenomenon in vitro, tissue decellularisation approaches have been developed, resulting in the generation of natural ECM scaffolds that have comparable physical and biochemical properties of the natural tissues and are currently gaining traction in tissue engineering and regenerative therapies due to the ease of standardised production, and constant availability. In this manuscript we report the successful generation of decellularised ECM-derived peptides from neural retina (decel NR) and retinal pigment epithelium (decel RPE), and their impact on differentiation of human pluripotent stem cells (hPSCs) to retinal organoids. We show that culture media supplementation with decel RPE and RPE-conditioned media (CM RPE) significantly increases the generation of rod photoreceptors, whilst addition of decel NR and decel RPE significantly enhances ribbon synapse marker expression and the light responsiveness of retinal organoids. Photoreceptor maturation, formation of correct synapses between retinal cells and recording of robust light responses from hPSC-derived retinal organoids remain unresolved challenges for the field of regenerative medicine. Enhanced rod photoreceptor differentiation, synaptogenesis and light response in response to addition of decellularised matrices from RPE and neural retina as shown herein provide a novel and substantial advance in generation of retinal organoids for drug screening, tissue engineering and regenerative medicine