GABAA presynaptic inhibition regulates the gain and kinetics of retinal output neurons

Output signals of neural circuits, including the retina, are shaped by a combination of excitatory and inhibitory signals. Inhibitory signals can act presynaptically on axon terminals to control neurotransmitter release and regulate circuit function. However, it has been difficult to study the role of presynaptic inhibition in most neural circuits due to lack of cell-type specific and receptor-type specific perturbations. In this study, we used a transgenic approach to selectively eliminate GABAA inhibitory receptors from select types of second order neurons - bipolar cells - in mouse retina and examined how this affects the light response properties of the well-characterized ON alpha ganglion cell retinal circuit. Selective loss of GABAA receptor-mediated presynaptic inhibition causes an enhanced sensitivity and slower kinetics of light-evoked responses from ON alpha ganglion cells thus highlighting the role of presynaptic inhibition in gain control and temporal filtering of sensory signals in a key neural circuit in the mammalian retina.

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C-terminal phosphorylation regulates the kinetics of a subset of melanopsin-mediated behaviors in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1611893114 ◽

2017 ◽

Vol 114 (10) ◽

pp. 2741-2746 ◽

Cited By ~ 15

Author(s):

Preethi Somasundaram ◽

Glenn R. Wyrick ◽

Diego Carlos Fernandez ◽

Alireza Ghahari ◽

Cindy M. Pinhal ◽

...

Keyword(s):

Ganglion Cells ◽

Light Response ◽

Circadian Phase ◽

Light Intensities ◽

C Terminus ◽

Phase Alignment ◽

Electrophysiological Measurements ◽

Virally Encoded ◽

Phototransduction Pathway ◽

Kinetics Of

Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and mediate several non–image-forming visual functions, including circadian photoentrainment and the pupillary light reflex (PLR). ipRGCs act as autonomous photoreceptors via the intrinsic melanopsin-based phototransduction pathway and as a relay for rod/cone input via synaptically driven responses. Under low light intensities, where only synaptically driven rod/cone input activates ipRGCs, the duration of the ipRGC response will be determined by the termination kinetics of the rod/cone circuits. Little is known, however, about the termination kinetics of the intrinsic melanopsin-based phototransduction pathway and its contribution to several melanopsin-mediated behaviors. Here, we show that C-terminal phosphorylation of melanopsin determines the recovery kinetics of the intrinsic melanopsin-based photoresponse in ipRGCs, the duration of the PLR, and the speed of reentrainment. In contrast, circadian phase alignment and direct effects of light on activity (masking) are not influenced by C-terminal phosphorylation of melanopsin. Electrophysiological measurements demonstrate that expression of a virally encoded melanopsin lacking all C-terminal phosphorylation sites (C terminus phosphonull) leads to a prolonged intrinsic light response. In addition, mice expressing the C terminus phosphonull in ipRGCs reentrain faster to a delayed light/dark cycle compared with mice expressing virally encoded WT melanopsin; however, the phase angle of entrainment and masking were indistinguishable. Importantly, a sustained PLR in the phosphonull animals is only observed at brighter light intensities that activate melanopsin phototransduction, but not at dimmer light intensities that activate only the rod/cone pathway. Taken together, our results highlight how the kinetics of the melanopsin photoresponse differentially regulate distinct light-mediated behaviors.

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Functional role of GABA in cat retina: II. Effects of GABAA antagonists

Visual Neuroscience ◽

10.1017/s0952523800008944 ◽

1995 ◽

Vol 12 (4) ◽

pp. 651-661 ◽

Cited By ~ 15

Author(s):

Thomas E. Frumkes ◽

Ralph Nelson ◽

Renate Pflug

Keyword(s):

Ganglion Cells ◽

Central Zone ◽

Amacrine Cells ◽

Cell Types ◽

Methyl Halides ◽

Cat Retina ◽

Kinetics Of ◽

Proximal Zone ◽

Slow Onset

AbstractPutative GABAergic mechanisms were studied in the cat retina by exogenous application of the GABAA antagonists picrotoxin (PTX), native bicuculline (BCC), and bicuculline methyl bromide (BCC MeBr). When recording intracellular responses from horizontal cells (HCs) and amacrine cells as well as electroretinograms (ERGs), drugs were added to the perfusate used to maintain the isolated eyecup; when recording extracellular spikes from ganglion cells of anesthetized cats, drugs were introduced by iontophoretic injection. Both PTX and BCC MeBr had relatively little influence upon the response properties of HCs. In contrast, native BCC tended to decrease the amplitude of and to slow the photic response to light onset and both to quicken and to increase the amplitude of response to light offset; in the presence of native BCC, HC responses were dominated by a prominent spike-like “Off-overshoot.” The influence of GABAA agonists upon HC responses was not blocked by GABAA antagonists. ERG b−wave amplitude was reduced both by PTX and by native BCC, but was not influenced by BCC MeBr. Latency (time to half-peak) was increased by low doses of native BCC, and to a lesser extent PTX but not BCC MeBr. Rod-amacrine On-transient responses were increased in amplitude by PTX. Extracellular recordings from On- and Off- X and Y ganglion cell types became considerably more transient with application of either PTX, native BCC, or BCC MeBr; this tendency was greater in Off-type ganglion cells. Collectively, these results strengthen conclusions from the previous paper suggesting that GABA serves to slow onset and offset kinetics of retinal neurons, making them more sustained and less phasic. They also suggest that in mammalian retina heterogeneous types of GABAA receptors exist, segregated into different zones: a distal zone, sensitive only to native BCC, a central zone sensitive to both native BCC and PTX, and a proximal zone sensitive to native BCC, BCC methyl halides (BCC MeH), and PTX. Only the proximal zone obeys conventional GABAA pharmacology.

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Receptive field properties of bipolar cell axon terminals in direction-selective sublaminas of the mouse retina

Journal of Neurophysiology ◽

10.1152/jn.00283.2014 ◽

2014 ◽

Vol 112 (8) ◽

pp. 1950-1962 ◽

Cited By ~ 29

Author(s):

Minggang Chen ◽

Seunghoon Lee ◽

Silvia J. H. Park ◽

Loren L. Looger ◽

Z. Jimmy Zhou

Keyword(s):

Receptive Field ◽

Ganglion Cells ◽

Amacrine Cells ◽

Direction Selectivity ◽

Bipolar Cells ◽

Visual Signals ◽

Mouse Retina ◽

Patch Clamp Recording ◽

Axon Terminals ◽

Starburst Amacrine Cells

Retinal bipolar cells (BCs) transmit visual signals in parallel channels from the outer to the inner retina, where they provide glutamatergic inputs to specific networks of amacrine and ganglion cells. Intricate network computation at BC axon terminals has been proposed as a mechanism for complex network computation, such as direction selectivity, but direct knowledge of the receptive field property and the synaptic connectivity of the axon terminals of various BC types is required in order to understand the role of axonal computation by BCs. The present study tested the essential assumptions of the presynaptic model of direction selectivity at axon terminals of three functionally distinct BC types that ramify in the direction-selective strata of the mouse retina. Results from two-photon Ca2+ imaging, optogenetic stimulation, and dual patch-clamp recording demonstrated that 1) CB5 cells do not receive fast GABAergic synaptic feedback from starburst amacrine cells (SACs); 2) light-evoked and spontaneous Ca2+ responses are well coordinated among various local regions of CB5 axon terminals; 3) CB5 axon terminals are not directionally selective; 4) CB5 cells consist of two novel functional subtypes with distinct receptive field structures; 5) CB7 cells provide direct excitatory synaptic inputs to, but receive no direct GABAergic synaptic feedback from, SACs; and 6) CB7 axon terminals are not directionally selective, either. These findings help to simplify models of direction selectivity by ruling out complex computation at BC terminals. They also show that CB5 comprises two functional subclasses of BCs.

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The formin Fmn2 is required for the development of an excitatory interneuron module in the zebrafish acoustic startle circuit

10.1101/2020.07.23.218032 ◽

2020 ◽

Cited By ~ 1

Author(s):

Dhriti Nagar ◽

Tomin K James ◽

Ratnakar Mishra ◽

Shrobona Guha ◽

Aurnab Ghose

Keyword(s):

Growth Cone ◽

Neurodevelopmental Disorders ◽

High Speed ◽

Neural Circuits ◽

Neural Circuit ◽

Video Recording ◽

Acoustic Startle ◽

Neuronal Cultures

ABSTRACTThe formin family member, Fmn2, is a neuronally enriched cytoskeletal remodelling protein conserved across vertebrates. Recent studies have implicated Fmn2 in neurodevelopmental disorders, including sensory processing dysfunction and intellectual disability in humans. Cellular characterization of Fmn2 in primary neuronal cultures has identified its function in the regulation of cell-substrate adhesion and consequently growth cone translocation. However, the role of Fmn2 in the development of neural circuits in vivo, and its impact on associated behaviours have not been tested.Using automated analysis of behaviour and systematic investigation of the associated circuitry, we uncover the role of Fmn2 in zebrafish neural circuit development. As reported in other vertebrates, the zebrafish ortholog of Fmn2 is also enriched in the developing zebrafish nervous system. We find that Fmn2 is required for the development of an excitatory interneuron pathway, the spiral fiber neuron, which is an essential circuit component in the regulation of the Mauthner cell-mediated acoustic startle response. Consistent with the loss of the spiral fiber neurons tracts, high-speed video recording revealed a reduction in the short latency escape events while responsiveness to the stimuli was unaffected.Taken together, this study provides evidence for a circuit-specific requirement of Fmn2 in eliciting an essential behaviour in zebrafish. Our findings underscore the importance of Fmn2 in neural development across vertebrate lineages and highlight zebrafish models in understanding neurodevelopmental disorders.SIGNIFICANCE STATEMENTFmn2 is a neuronally enriched cytoskeletal remodelling protein linked to neurodevelopment and cognitive disorders in humans. Recent reports have characterized its function in growth cone motility and chemotaxis in cultured primary neurons. However, the role of Fmn2 in the development of neural circuits in vivo and its implications in associated behaviours remain unexplored. This study shows that Fmn2 is required for the development of neuronal processes in the acoustic startle circuit to ensure robust escape responses to aversive stimuli in zebrafish. Our study underscores the crucial role of the non-diaphanous formin, Fmn2, in establishing neuronal connectivity and related behaviour in zebrafish.

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Subtype-dependent postnatal development of direction- and orientation-selective retinal ganglion cells in mice

Journal of Neurophysiology ◽

10.1152/jn.00320.2014 ◽

2014 ◽

Vol 112 (9) ◽

pp. 2092-2101 ◽

Cited By ~ 13

Author(s):

Hui Chen ◽

Xiaorong Liu ◽

Ning Tian

Keyword(s):

Postnatal Development ◽

Retinal Ganglion Cells ◽

Ganglion Cells ◽

Light Response ◽

Orientation Selectivity ◽

Mouse Retina ◽

Retinal Ganglion ◽

Tuning Width ◽

Eye Opening ◽

Synaptic Mechanisms

The direction-selective ganglion cells (DSGCs) and orientation-selective ganglion cells (OSGCs) encode the directional and the orientational information of a moving object, respectively. It is unclear how DSGCs and OSGCs mature in the mouse retina during postnatal development. Here we investigated the development of DSGCs and OSGCs after eye-opening. We show that 1) DSGCs and OSGCs are present at postnatal day 12 (P12), just before eye-opening; 2) the fractions of both DSGCs and OSGCs increase from P12 to P30; 3) the development of DSGCs and OSGCs is subtype dependent; and 4) direction and orientation selectivity are two separate features of retinal ganglion cells (RGCs) in the mouse retina. We classified RGCs into different functional subtypes based on their light response properties. Compared with P12, the direction and orientation selectivity of ON-OFF RGCs but not ON RGCs became stronger at P30. The tuning width of DSGCs for both ON and ON-OFF subtypes decreased with age. For OSGCs, we divided them into non-direction-selective (non-DS) OSGCs and direction-selective OSGCs (DS&OSGCs). For DS&OSGCs, we found that there was no correlation between the direction and orientation selectivity, and that the tuning width of both ON and ON-OFF subtypes remained unchanged with age. For non-DS OSGCs, the tuning width of ON but not ON-OFF subtype decreased with development. These findings provide a foundation to reveal the molecular and synaptic mechanisms underlying the development of the direction and orientation selectivity in the retina.

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Photoreception

Sensory Transduction ◽

10.1093/oso/9780198835028.003.0009 ◽

2019 ◽

pp. 178-216

Author(s):

Gordon L. Fain

Keyword(s):

Light Adaptation ◽

Ganglion Cells ◽

Light Exposure ◽

Bright Light ◽

Light Response ◽

Sensory Transduction ◽

Individual Treatment ◽

Rods And Cones ◽

Response Light

“Photoreception” is the ninth chapter of the book Sensory Transduction and begins with general mechanisms of light detection, photopigment activation, and the variety of pathways of phototransduction using the scallop eye as an example. There is then a thorough treatment of the photoreceptors of arthropods, particularly those of Limulus and Drosophila. Following a description of photoreceptor anatomy, the chapter describes transduction in these arthropods including photoreceptor channels and the role of Ca2+ in the regulation of gain and turnoff. It then proceeds to vertebrate rods and cones, with individual treatment of the topics of transduction in vertebrate photoreceptors, the ion channels of rods and cones, the description and measurement of the photocurrent, pathways responsible for shutting down the light response, light adaptation, pigment renewal, and the recovery of sensitivity after bright light exposure. It concludes with transduction in intrinsically photosensitive retinal ganglion cells.

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Mechanisms creating transient and sustained photoresponses in mammalian retinal ganglion cells

The Journal of General Physiology ◽

10.1085/jgp.201611720 ◽

2017 ◽

Vol 149 (3) ◽

pp. 335-353 ◽

Cited By ~ 8

Author(s):

Xiwu Zhao ◽

Aaron N. Reifler ◽

Melanie M. Schroeder ◽

Elizabeth R. Jaeckel ◽

Andrew P. Chervenak ◽

...

Keyword(s):

Retinal Ganglion Cells ◽

Presynaptic Inhibition ◽

Ganglion Cells ◽

Glutamate Uptake ◽

Bipolar Cells ◽

Retinal Ganglion ◽

Light Responses ◽

Comprehensive Survey ◽

Underlying Mechanisms ◽

Kinetics Of

Retinal neurons use sustained and transient light responses to encode visual stimuli of different frequency ranges, but the underlying mechanisms remain poorly understood. In particular, although earlier studies in retinal ganglion cells (RGCs) proposed seven potential mechanisms, all seven have since been disputed, and it remains unknown whether different RGC types use different mechanisms or how many mechanisms are used by each type. Here, we conduct a comprehensive survey in mice and rats of 12 candidate mechanisms that could conceivably produce tonic rod/cone-driven ON responses in intrinsically photosensitive RGCs (ipRGCs) and transient ON responses in three types of direction-selective RGCs (TRHR+, Hoxd10+ ON, and Hoxd10+ ON-OFF cells). We find that the tonic kinetics of ipRGCs arises from their substantially above-threshold resting potentials, input from sustained ON bipolar cells, absence of amacrine cell inhibition of presynaptic ON bipolar cells, and mGluR7-mediated maintenance of light-evoked glutamatergic input. All three types of direction-selective RGCs receive input from transient ON bipolar cells, and each type uses additional strategies to promote photoresponse transience: presynaptic inhibition and dopaminergic modulation for TRHR+ cells, center/surround antagonism and relatively negative resting potentials for Hoxd10+ ON cells, and presynaptic inhibition for Hoxd10+ ON-OFF cells. We find that the sustained nature of ipRGCs’ rod/cone-driven responses depends neither on melanopsin nor on N-methyl-d-aspartate (NMDA) receptors, whereas the transience of the direction-selective cells’ responses is influenced neither by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor desensitization nor by glutamate uptake. For all cells, we further rule out spike frequency adaptation and intracellular Ca2+ as determinants of photoresponse kinetics. In conclusion, different RGC types use diverse mechanisms to produce sustained or transient light responses. Parenthetically, we find evidence in both mice and rats that the kinetics of light-induced mGluR6 deactivation determines whether an ON bipolar cell responds tonically or transiently to light.

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Linear and nonlinear chromatic integration in the mouse retina

10.1101/2020.06.29.176859 ◽

2020 ◽

Author(s):

Mohammad Hossein Khani ◽

Tim Gollisch

Keyword(s):

Visual Information ◽

Neural Circuit ◽

Ganglion Cells ◽

The Other ◽

Mouse Retina ◽

Natural Scenes ◽

Spatial Integration ◽

Time Space ◽

Cone Type ◽

Classical Studies

AbstractThe computation performed by a neural circuit depends on how it integrates its input signals into an output of its own. In the retina, ganglion cells integrate visual information over time, space, and chromatic channels. Unlike the former two, chromatic integration in the retina is largely unexplored. Analogous to classical studies of spatial integration, we here studied chromatic integration in mouse retina by identifying chromatic stimuli for which activation from one cone type is maximally balanced by deactivation in the other cone type. This revealed nonlinear chromatic integration in subsets of On, Off, and On-Off ganglion cells. Nonlinear On cells differed from the other two classes by displaying response suppression rather than activation under balanced chromatic stimulation. Furthermore, nonlinear chromatic integration occurs independently of nonlinear spatial integration, depends on inhibitory signals from the receptive field surround, and may provide information about chromatic boundaries, such as the skyline in natural scenes.

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IDENTIFICATION OF A NOVEL BDNF-SPECIFIC CORTICOSTRIATAL CIRCUITRY

10.1101/2021.08.26.457842 ◽

2021 ◽

Author(s):

Yann Ehinger ◽

Drishti Soneja ◽

Khanhky Phamluong ◽

Dorit Ron

Keyword(s):

Motor Cortex ◽

Orbitofrontal Cortex ◽

Neural Circuit ◽

Dorsal Striatum ◽

Medial Part ◽

Striatal Neurons ◽

Bdnf Expression ◽

Axon Terminals ◽

Bdnf Signaling

BDNF is released from axon terminals originating in the cerebral cortex onto striatal neurons. Here, we characterized BDNF in the corticostriatal circuitry. First, we utilized Bdnf-Cre and Ribotag transgenic mouse lines to label BDNF-positive cells in the cortex, and detected BDNF expression in the motor cortex, medial prefrontal cortex (mPFC) and the orbitofrontal cortex (OFC). Next, we used a retrograde viral tracing strategy, in combination with Bdnf-Cre knockin mice, to map the cortical outputs of BDNF neurons in the dorsal striatum. We found that the BDNF-positive prefrontal regions differentially project to the dorsal striatum. Specifically, BDNF-expressing neurons located in the mPFC project to both dorsolateral striatum (DLS) and dorsomedial striatum (DMS), and those located in the motor cortex project to the DLS. Surprisingly however, the BDNF-expressing OFC neurons differentially target the dorsal striatum depending on their mediolateral location. Specifically, the DMS is mainly innervated by the medial part of the OFC (mOFC) whereas, the DLS receives projections specifically from the ventrolateral region of the OFC (vlOFC). Next, using an anterograde viral tracing strategy, we confirmed the presence of a BDNF-specific vlOFC-DLS circuit. Finally, we show that overexpression of BDNF in the vlOFC activates TrkB signaling specifically in the DLS but not in the DMS demonstrating the functionality of this circuit. Our study uncovers a previously unknown neural circuit composed of BDNF-positive vlOFC neurons projecting to the DLS. These findings could have important implications for the role of BDNF signaling in the OFC as well as in other corticostriatal circuitries.

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Trans-Axonal Signaling in Neural Circuit Wiring

International Journal of Molecular Sciences ◽

10.3390/ijms21145170 ◽

2020 ◽

Vol 21 (14) ◽

pp. 5170 ◽

Cited By ~ 1

Author(s):

Olivia Spead ◽

Fabienne E. Poulain

Keyword(s):

Molecular Mechanisms ◽

Neural Circuits ◽

Neural Circuit ◽

Target Selection ◽

Synaptic Connectivity ◽

Recent Advances ◽

Complex Process ◽

Circuit Formation

The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon–environment and axon–target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon–axon interactions during the different steps of neural circuit formation.

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