-
Bioscience Reports Jul 2022Rbfox1 is a multifunctional RNA-binding protein that regulates alternative splicing, transcription, mRNA stability, and translation. Rbfox1 is an important regulator of...
Rbfox1 is a multifunctional RNA-binding protein that regulates alternative splicing, transcription, mRNA stability, and translation. Rbfox1 is an important regulator of gene networks involved in neurogenesis and neuronal function. Disruption of Rbfox function has been associated with several neurodevelopmental and neuropsychiatric disorders. We have shown earlier that Rbfox1 is expressed in retinal ganglion and amacrine cells (ACs) and that its down-regulation in adult mouse retinas leads to deficiency of depth perception. In the present study, we used several markers of ACs, including gamma-aminobutyric acid (GABA), choline acetyltransferase (ChAT), neuropeptide Y (NPY), glycine transporter (GlyT1), and vesicular glutamate transporter 3 (VGlut3) to identify types of ACs that express Rbfox1. Expression of Rbfox1 was observed predominantly in GABAergic ACs located in the inner nuclear layer (INL) and ganglion cell layer (GCL). All GABAergic/cholinergic starburst ACs and virtually all NPY-positive GABAergic ACs were also Rbfox1-positive. Among glycinergic ACs, a sparse population of Rbfox1/VGlut3-positive cells was identified, indicating that Rbfox1 is expressed in a very small population of glycinergic ACs. These data contribute to our understanding about molecular differences between various types of amacrine cells and the cell-specific gene networks regulated by Rbfox1.
Topics: Amacrine Cells; Animals; Choline O-Acetyltransferase; Mice; RNA Splicing Factors; Retina; Retinal Ganglion Cells
PubMed: 35730583
DOI: 10.1042/BSR20220497 -
Proceedings of the National Academy of... Jun 2009The vertebrate retina uses diverse neuronal cell types arrayed into complex neural circuits to extract, process, and relay information from the visual scene to the...
The vertebrate retina uses diverse neuronal cell types arrayed into complex neural circuits to extract, process, and relay information from the visual scene to the higher order processing centers of the brain. Amacrine cells, a class of interneurons, are thought to mediate much of the processing of the visual signal that occurs within the retina. Although amacrine cells display extensive morphological diversity, the molecular nature of this diversity is largely unknown. Furthermore, it is not known how this diversity arises during development. Here, we have combined in vivo genetic labeling, single cell genome-wide expression profiling, and classical birthdating to (i) identify specific molecular types of amacrine cells, (ii) demonstrate the molecular diversity of the amacrine cell class, and (iii) show that amacrine cell diversity arises at least in part through temporal patterning.
Topics: Amacrine Cells; Animals; Gene Expression Profiling; Mice; Neurogenesis; Retina
PubMed: 19470466
DOI: 10.1073/pnas.0903264106 -
The Journal of Comparative Neurology Aug 2021In primates, broad thorny retinal ganglion cells are highly sensitive to small, moving stimuli. They have tortuous, fine dendrites with many short, spine-like branches...
In primates, broad thorny retinal ganglion cells are highly sensitive to small, moving stimuli. They have tortuous, fine dendrites with many short, spine-like branches that occupy three contiguous strata in the middle of the inner plexiform layer. The neural circuits that generate their responses to moving stimuli are not well-understood, and that was the goal of this study. A connectome from central macaque retina was generated by serial block-face scanning electron microscopy, a broad thorny cell was reconstructed, and its synaptic inputs were analyzed. It received fewer than 2% of its inputs from both ON and OFF types of bipolar cells; the vast majority of its inputs were from amacrine cells. The presynaptic amacrine cells were reconstructed, and seven types were identified based on their characteristic morphology. Two types of narrow-field cells, knotty bistratified Type 1 and wavy multistratified Type 2, were identified. Two types of medium-field amacrine cells, ON starburst and spiny, were also presynaptic to the broad thorny cell. Three types of wide-field amacrine cells, wiry Type 2, stellate wavy, and semilunar Type 2, also made synapses onto the broad thorny cell. Physiological experiments using a macaque retinal preparation in vitro confirmed that broad thorny cells received robust excitatory input from both the ON and the OFF pathways. Given the paucity of bipolar cell inputs, it is likely that amacrine cells provided much of the excitatory input, in addition to inhibitory input.
Topics: Amacrine Cells; Animals; Connectome; Macaca; Macaca nemestrina; Male; Retina; Retinal Ganglion Cells; Synapses
PubMed: 33843050
DOI: 10.1002/cne.25156 -
Current Biology : CB Jun 2022The detection of motion direction is a fundamental visual function and a classic model for neural computation. In the non-primate retina, direction selectivity arises in...
The detection of motion direction is a fundamental visual function and a classic model for neural computation. In the non-primate retina, direction selectivity arises in starburst amacrine cell (SAC) dendrites, which provide selective inhibition to direction-selective retinal ganglion cells (dsRGCs). Although SACs are present in primates, their connectivity and the existence of dsRGCs remain open questions. Here, we present a connectomic reconstruction of the primate ON SAC circuit from a serial electron microscopy volume of the macaque central retina. We show that the structural basis for the SACs' ability to confer directional selectivity on postsynaptic neurons is conserved. SACs selectively target a candidate homolog to the mammalian ON-sustained dsRGCs that project to the accessory optic system (AOS) and contribute to gaze-stabilizing reflexes. These results indicate that the capacity to compute motion direction is present in the retina, which is earlier in the primate visual system than classically thought.
Topics: Amacrine Cells; Animals; Connectome; Dendrites; Mammals; Primates; Retina; Retinal Ganglion Cells; Synapses
PubMed: 35588744
DOI: 10.1016/j.cub.2022.04.056 -
The Journal of Neuroscience : the... Sep 2015Much of the computational power of the retina derives from the activity of amacrine cells, a large and diverse group of GABAergic and glycinergic inhibitory...
Much of the computational power of the retina derives from the activity of amacrine cells, a large and diverse group of GABAergic and glycinergic inhibitory interneurons. Here, we identify an ON-type orientation-selective, wide-field, polyaxonal amacrine cell (PAC) in the rabbit retina and demonstrate how its orientation selectivity arises from the structure of the dendritic arbor and the pattern of excitatory and inhibitory inputs. Excitation from ON bipolar cells and inhibition arising from the OFF pathway converge to generate a quasi-linear integration of visual signals in the receptive field center. This serves to suppress responses to high spatial frequencies, thereby improving sensitivity to larger objects and enhancing orientation selectivity. Inhibition also regulates the magnitude and time course of excitatory inputs to this PAC through serial inhibitory connections onto the presynaptic terminals of ON bipolar cells. This presynaptic inhibition is driven by graded potentials within local microcircuits, similar in extent to the size of single bipolar cell receptive fields. Additional presynaptic inhibition is generated by spiking amacrine cells on a larger spatial scale covering several hundred microns. The orientation selectivity of this PAC may be a substrate for the inhibition that mediates orientation selectivity in some types of ganglion cells. Significance statement: The retina comprises numerous excitatory and inhibitory circuits that encode specific features in the visual scene, such as orientation, contrast, or motion. Here, we identify a wide-field inhibitory neuron that responds to visual stimuli of a particular orientation, a feature selectivity that is primarily due to the elongated shape of the dendritic arbor. Integration of convergent excitatory and inhibitory inputs from the ON and OFF visual pathways suppress responses to small objects and fine textures, thus enhancing selectivity for larger objects. Feedback inhibition regulates the strength and speed of excitation on both local and wide-field spatial scales. This study demonstrates how different synaptic inputs are regulated to tune a neuron to respond to specific features in the visual scene.
Topics: Amacrine Cells; Animals; Axons; Dendrites; Evoked Potentials, Visual; GABA Agents; Nerve Net; Orientation; Patch-Clamp Techniques; Photic Stimulation; Presynaptic Terminals; Rabbits; Receptors, GABA; Retina; Retinal Bipolar Cells; Retinal Ganglion Cells; Synapses; Visual Fields
PubMed: 26424882
DOI: 10.1523/JNEUROSCI.1712-15.2015 -
Investigative Ophthalmology & Visual... May 2018The combined action of the activating protein-2 (AP-2) transcription factors, AP-2α and AP-2β, is important in early retinal development, specifically in the formation...
PURPOSE
The combined action of the activating protein-2 (AP-2) transcription factors, AP-2α and AP-2β, is important in early retinal development, specifically in the formation of horizontal cells. However, in previous studies, it was not possible to analyze postnatal development and function of additional retinal subtypes.
METHODS
We used a double conditional deletion of AP-2α and AP-2β from the retina to further examine the combinatory role of these genes in retinal cell patterning and function in postnatal adult mice as measured by Voronoi domain area and nearest-neighbor distance spatial analyses and ERGs, respectively.
RESULTS
Conditional deletion of both AP-2α and AP-2β from the retina resulted in a variety of abnormalities, including the absence of horizontal cells, defects in the photoreceptor ribbons in which synapses failed to form, along with evidence of aberrant amacrine cell arrangement. Although no significant changes in amacrine cell population numbers were observed in the double mutants, significant irregularities in the mosaic patterning of amacrine cells was observed as demonstrated by both Voronoi domain areas and nearest-neighbor distances analyses. These changes were further accompanied by an alteration in the retinal response to light as recorded by ERGs. In particular, in the double-mutant mice lacking AP-2α and AP-2β, the b-wave amplitude, representative of interneuron signal processing, was significantly reduced compared with control littermates.
CONCLUSIONS
Together these findings demonstrate the requirement for both AP-2α and AP-2β in proper amacrine mosaic patterning and a normal functional light response in the retina.
Topics: Amacrine Cells; Animals; Animals, Newborn; Base Sequence; Cell Count; DNA; Electroretinography; Female; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation, Developmental; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Models, Animal; Retina; Sequence Deletion; Transcription Factor AP-2
PubMed: 29715367
DOI: 10.1167/iovs.17-23283 -
The Journal of Comparative Neurology Dec 2009The mammalian retina contains six major cell types, several of which are divided into multiple molecularly and morphologically distinct subtypes. To understand how... (Comparative Study)
Comparative Study
The mammalian retina contains six major cell types, several of which are divided into multiple molecularly and morphologically distinct subtypes. To understand how subtype diversity arises during development, we focused on amacrine interneurons in the mouse retina; approximately 30 amacrine subtypes have been identified in mammals. We used antibody markers to identify the two main amacrine subsets--GABAergic and glycinergic--and further subdivided these groups into smaller subsets based on expression of neurotransmitter and transcription factor markers. We then used bromodeoxyuridine (BrdU) labeling to see whether amacrine subsets are born (become postmitotic) at different times, as is the case for lamina-specified subsets of cortical projection neurons. We found that GABAergic amacrines are generated on average 2-3 days before glycinergic amacrines. Moreover, subsets of GABAergic amacrines are born at distinct times. We also found a strong correlation between amacrine cell birthday and soma position in the mature retina, another point of similarity with cortical projection neurons. This relationship raised the possibility that amacrine subtype identity is determined by signals that uncommitted cells receive after they migrate to their destinations. However, cells labeled with BrdU in vivo, then dissociated and allowed to develop in vitro, acquired the amacrine subtype-specific markers appropriate for their birthdays, supporting the idea that they become specified near the time and place of their birth. Together, our results suggest that the birthdays of amacrine cells independently specify their destinations and subtype identities.
Topics: Amacrine Cells; Animals; Cell Differentiation; Cellular Senescence; Glycine; Mice; Neurogenesis; Retina; Time Factors; gamma-Aminobutyric Acid
PubMed: 19827163
DOI: 10.1002/cne.22200 -
Visual Neuroscience Jan 2018The orderly spacing of retinal neurons is commonly regarded as a characteristic feature of retinal nerve cell populations. Exemplars of this property include the...
The orderly spacing of retinal neurons is commonly regarded as a characteristic feature of retinal nerve cell populations. Exemplars of this property include the horizontal cells and the cholinergic amacrine cells, where individual cells minimize the proximity to like-type neighbors, yielding regularity in the patterning of their somata. Recently, two types of retinal bipolar cells in the mouse retina were shown to exhibit an order in their somal patterning no different from density-matched simulations constrained by soma size but being otherwise randomly distributed. The present study has now extended this finding to a type of retinal amacrine cell, the AII amacrine cell. Voronoi domain analysis revealed the patterning in the population of AII amacrine somata to be no different from density-matched and soma-size-constrained random simulations, while analysis of the density recovery profile showed AII amacrine cells to exhibit a minimal intercellular spacing identical to that for those random simulations: AII amacrine somata were positioned side-by-side as often as chance would predict. Regularity indexes and packing factors (PF) were far lower than those achieved by either the horizontal cells or cholinergic amacrine cells, with PFs also being comparable to those derived from the constrained random simulations. These results extend recent findings that call into question the widespread assumption that all types of retinal neurons are assembled as regular somal arrays, and have implications for the way in which AII amacrine cells must distribute their processes to ensure a uniform coverage of the retinal surface.
Topics: Amacrine Cells; Animals; Cell Body; Cell Count; Dendrites; Mice; Mice, Inbred C57BL; Retinal Bipolar Cells
PubMed: 29905123
DOI: 10.1017/S0952523817000347 -
Experimental Eye Research Dec 2018Many types of retinal neuron modulate the distribution of their processes to ensure a uniform coverage of the retinal surface. Dendritic field area, for instance, is...
Many types of retinal neuron modulate the distribution of their processes to ensure a uniform coverage of the retinal surface. Dendritic field area, for instance, is inversely related to the variation in cellular density for many cell types, observed either across retinal eccentricity or between different strains of mice that differ in cell number. Dopaminergic amacrine (DA) cells, by contrast, have dendritic arbors that bear no spatial relationship to the presence of their immediate homotypic neighbors, yet it remains to be determined whether their coverage upon the retina, as a population, is conserved across variation in their total number. The present study assessed the overall density of the dopaminergic plexus in the inner plexiform layer in the presence of large variation in the total number of DA cells, as well as their retinal dopamine content, to determine whether either of these features is conserved. We first compared these traits between two strains of mice (C57BL/6J and A/J) that exhibit a two-fold difference in DA cell number. We subsequently examined these same traits in littermate mice for which the pro-apoptotic Bax gene was either intact or knocked out, yielding a five-fold difference in DA cell number. In both comparisons, we found greater plexus density and DA content in the strain or condition with the greater number of DA cells. The population of DA cells, therefore, does not appear to self-regulate its process coverage to achieve a constant density as the DA mosaic is established during development, nor its functional dopamine content in maturity.
Topics: Amacrine Cells; Animals; Cell Count; Chromatography, High Pressure Liquid; Dendrites; Dopamine; Dopaminergic Neurons; Mice; Mice, Inbred C57BL; Mice, Knockout; Retina; bcl-2-Associated X Protein
PubMed: 30240584
DOI: 10.1016/j.exer.2018.09.008 -
Cell Reports Oct 2022Midget and parasol ganglion cells (GCs) represent the major output channels from the primate eye to the brain. On-type midget and parasol GCs exhibit a higher background...
Midget and parasol ganglion cells (GCs) represent the major output channels from the primate eye to the brain. On-type midget and parasol GCs exhibit a higher background spike rate and thus can respond more linearly to contrast changes than their Off-type counterparts. Here, we show that a calcium-permeable AMPA receptor (CP-AMPAR) antagonist blocks background spiking and sustained light-evoked firing in On-type GCs while preserving transient light responses. These effects are selective for On-GCs and are occluded by a gap-junction blocker suggesting involvement of AII amacrine cells (AII-ACs). Direct recordings from AII-ACs, cobalt uptake experiments, and analyses of transcriptomic data confirm that CP-AMPARs are expressed by primate AII-ACs. Overall, our data demonstrate that under some background light levels, CP-AMPARs at the rod bipolar to AII-AC synapse drive sustained signaling in On-type GCs and thus contribute to the more linear contrast signaling of the primate On- versus Off-pathway.
Topics: Amacrine Cells; Animals; Calcium; Cobalt; Primates; Receptors, AMPA; Receptors, Calcium-Sensing; Retina
PubMed: 36223749
DOI: 10.1016/j.celrep.2022.111484