Dopamine D1 receptor modulation of calcium channel currents in horizontal cells of mouse retina

Horizontal cells form the first laterally interacting network of inhibitory interneurons in the retina. Dopamine released onto horizontal cells under photic and circadian control modulates horizontal cell function. Using isolated, identified horizontal cells from a connexin-57-iCre × ROSA26-tdTomato transgenic mouse line, we investigated dopaminergic modulation of calcium channel currents ( ICa) with whole cell patch-clamp techniques. Dopamine (10 μM) blocked 27% of steady-state ICa, an action blunted to 9% in the presence of the L-type Ca channel blocker verapamil (50 μM). The dopamine type 1 receptor (D1R) agonist SKF38393 (20 μM) inhibited ICa by 24%. The D1R antagonist SCH23390 (20 μM) reduced dopamine and SKF38393 inhibition. Dopamine slowed ICa activation, blocking ICa by 38% early in a voltage step. Enhanced early inhibition of ICa was eliminated by applying voltage prepulses to +120 mV for 100 ms, increasing ICa by 31% and 11% for early and steady-state currents, respectively. Voltage-dependent facilitation of ICa and block of dopamine inhibition after preincubation with a Gβγ-blocking peptide suggested involvement of Gβγ proteins in the D1R-mediated modulation. When the G protein activator guanosine 5′- O-(3-thiotriphosphate) (GTPγS) was added intracellularly, ICa was smaller and showed the same slowed kinetics seen during D1R activation. With GTPγS in the pipette, additional block of ICa by dopamine was only 6%. Strong depolarizing voltage prepulses restored the GTPγS-reduced early ICa amplitude by 36% and steady-state ICa amplitude by 3%. These results suggest that dopaminergic inhibition of ICa via D1Rs is primarily mediated through the action of Gβγ proteins in horizontal cells.

Download Full-text

Nitric oxide and cGMP modulate retinal glutamate receptors

Journal of Neurophysiology ◽

10.1152/jn.1996.76.4.2307 ◽

1996 ◽

Vol 76 (4) ◽

pp. 2307-2315 ◽

Cited By ~ 45

Author(s):

D. G. McMahon ◽

L. V. Ponomareva

Keyword(s):

Nitric Oxide ◽

Glutamate Receptors ◽

Horizontal Cell ◽

Synaptic Function ◽

Horizontal Cells ◽

Glutamate Excitotoxicity ◽

No Donors ◽

Receptor Modulation ◽

Cell Recording ◽

Endogenous Nitric Oxide

1. In the retina, as in other regions of the vertebrate central nervous system, glutamate receptors mediate excitatory chemical synaptic transmission and are a critical site for the regulation of cellular communication. In this study, retinal horizontal cells from the hybrid less were dissociated in cell culture, voltage clamped by the whole cell recording technique, and the currents evoked by application of excitatory amino acids recorded. 2. Responses to glutamate and its agonist kainate were reduced by approximately 50% in the presence of the nitric oxide (NO) donors sodium nitroprusside and S-nitroso-N-acetylpenicillamine. The effect of these compounds was blocked by the NO scavenger hemoglobin. 3. This effect of NO donors on kainate currents could be mimicked by the application of a membrane permeable guanosine 3',5'-cyclic monophosphate (cGMP) analogue, 8-Br-cGMP. The NO effect was also blocked by application of the guanylate cyclase inhibitor LY-83583, and by a protein kinase G inhibitor peptide. 4. In H1-type horizontal cells, stimulation of endogenous nitric oxide synthase with L-arginine reduced kainate responses, whereas application of D-arginine had no effect. 5. This receptor modulation mechanism may act in concert with other pre- and postsynaptic mechanisms to modify horizontal cell synaptic function according to the adaptational state of the retina and also may protect horizontal cells from glutamate excitotoxicity.

Download Full-text

Effects of estrogens on Ca channels in myometrial cells isolated from pregnant rats

AJP Cell Physiology ◽

10.1152/ajpcell.1995.268.1.c64 ◽

1995 ◽

Vol 268 (1) ◽

pp. C64-C69 ◽

Cited By ~ 30

Author(s):

T. Yamamoto

Keyword(s):

Steady State ◽

Ca Channel ◽

Ca Channels ◽

Inhibitory Effects ◽

Inactivation Curve ◽

Pregnant Rat ◽

Negative Direction ◽

Myometrial Cells ◽

Steady State Inactivation ◽

Channel Currents

Whole cell patch-clamp techniques were applied to cultured smooth muscle cells isolated from the longitudinal layer of the late pregnant rat myometrium. Effects of estrogens on Ca channels were examined. Inhibitory effects of beta-estradiol (1 microM) on Ca channel currents were recognized. The inhibitory effects of beta-estradiol depended on holding potentials. beta-Estradiol shifted the steady-state inactivation curve in the negative direction by 7 mV at mid potential (n = 9). Diethylstilbestrol, a synthetic estrogen, gave similar effects on Ca channel currents at lower concentration (2 microM) to those of beta-estradiol. Strong inhibitory effects on Ca channel currents were obtained by higher concentration (20 microM). Diethylstilbestrol shifted the steady-state inactivation curve in the negative direction by 7 mV at mid potential (n = 5). The results indicate that estrogens influence the voltage dependency and the whole cell conductance of Ca channels of pregnant rat myometrial cells. The acute effect of estrogens may cause both electrical and mechanical depression of myometrium.

Download Full-text

Local signals in mouse horizontal cell dendrites

10.1101/143909 ◽

2017 ◽

Cited By ~ 1

Author(s):

Camille A. Chapot ◽

Christian Behrens ◽

Luke E. Rogerson ◽

Tom Baden ◽

Sinziana Pop ◽

...

Keyword(s):

Glutamate Release ◽

Horizontal Cell ◽

Horizontal Cells ◽

Single Type ◽

Mouse Retina ◽

Gabaergic Interneuron ◽

List Type ◽

Cone Photoreceptor ◽

Cone Photoreceptors ◽

Temporal Properties

SummaryThe mouse retina contains a single type of horizontal cell, a GABAergic interneuron that samples from all cone photoreceptors within reach and modulates their glutamatergic output via parallel feedback mechanisms. Because horizontal cells form an electrically-coupled network, they have been implicated in global signal processing, such as large scale contrast enhancement. Recently, it has been proposed that horizontal cells can also act locally at the level of individual cone photoreceptors. To test this possibility physiologically, we used two-photon microscopy to record light stimulus-evoked Ca2+signals in cone axon terminals and horizontal cell dendrites as well as glutamate release in the outer plexiform layer. By selectively stimulating the two mouse cone opsins with green and UV light, we assessed whether signals from individual cones remain “isolated” within horizontal cell dendritic tips, or whether they spread across the dendritic arbour. Consistent with the mouse‘s opsin expression gradient, we found that the Ca2+signals recorded from dendrites of dorsal horizontal cells were dominated by M- and those of ventral horizontal cells by S-opsin activation. The signals measured in neighbouring horizontal cell dendritic tips varied markedly in their chromatic preference, arguing against global processing. Rather, our experimental data and results from biophysically realistic modelling support the idea that horizontal cells can process cone input locally, extending the “classical” view of horizontal cells function. Pharmacologically removing horizontal cells from the circuitry reduced the sensitivity of the cone signal to low frequencies, suggesting that local horizontal cell feedback shapes the temporal properties of cone output.HighlightsLight-evoked Ca2+signals in horizontal cell dendrites reflect opsin gradientChromatic preferences in neighbouring dendritic tips vary markedlyMouse horizontal cells process cone photoreceptor input locallyLocal horizontal cell feedback shapes the temporal properties of cone outputeTOC BlurbChapot et al. show that local light responses in mouse horizontal cell dendrites inherit properties, including chromatic preference, from the presynaptic cone photoreceptor, suggesting that their dendrites can provide “private” feedback to cones, for instance, to shape the temporal filtering properties of the cone synapse.

Download Full-text

Whole cell and single-channel properties of a unique voltage-activated sustained calcium current identified in teleost retinal horizontal cells

Journal of Neurophysiology ◽

10.1152/jn.1996.75.2.609 ◽

1996 ◽

Vol 75 (2) ◽

pp. 609-619 ◽

Cited By ~ 12

Author(s):

C. L. Pfeiffer-Linn ◽

E. M. Lasater

Keyword(s):

Calcium Channel ◽

Calcium Current ◽

Single Channel ◽

Horizontal Cell ◽

Horizontal Cells ◽

Unique Type ◽

Whole Cell ◽

White Bass ◽

Cell Current ◽

P Type

1. A voltage-activated, sustained calcium current in white bass retinal cone horizontal cells was characterized on the basis of electrophysiological and pharmacological criteria. Studies were performed with the use of a combination of whole cell and single-channel analysis of outside-out excised patches from isolated, cultured retinal horizontal cells. 2. We found that the white bass sustained calcium channel represents a unique type of calcium channel. On the basis of our analysis, it does not fall into any current classification scheme. The horizontal cell channel shares some biophysical and pharmacological properties with the typical high-voltage-activated L-type channel, but it also has features in common with the P-type channel. 3. The biophysical characteristics of the channel were most typical of an L-type channel. It activated above -30 mV membrane potential and only very slowly inactivated. It had a single-channel conductance of 25 pS. 4. Like the typical L-type current, the horizontal cell current was sensitive to the dihydropyridine agonist Bay K 8644. It prolonged the channel open time, which resulted in a large increase in macroscopic current flow into the cell. However, unlike the typical L current, dihydropyridine antagonists (nifedipine, nimodipine, etc.) as well as the specific L-channel inhibitor diltiazem were only moderately effective at best. 5. In a previous study, we found the current was antagonized by a factor found in funnel-web spider toxin. Here we show that the current is completely blocked by low doses of omega-agatoxin IVA. These are characteristics of the P-type calcium channel. But unlike the P current, the horizontal cell current is relatively insensitive to low or high doses of omega-conotoxin MVIIC. 6. The overall combination of calcium channel characteristics sets apart the calcium channel in bass horizontal cells from previously described channels. It appears to be a unique, tissue-specific ion channel, which we have labeled the PL channel.

Download Full-text

Electrophysiological Properties of Mouse Horizontal Cell GABAA Receptors

Journal of Neurophysiology ◽

10.1152/jn.00284.2004 ◽

2004 ◽

Vol 92 (5) ◽

pp. 2789-2801 ◽

Cited By ~ 33

Author(s):

Andreas Feigenspan ◽

Reto Weiler

Keyword(s):

Single Channel ◽

Horizontal Cell ◽

Chloride Ions ◽

Horizontal Cells ◽

Hill Coefficient ◽

Mouse Retina ◽

Patch Clamp Technique ◽

Open Probability ◽

Steady State Current ◽

Single Channel Currents

GABA-induced currents have been characterized in isolated horizontal cells from lower vertebrates but not in mammalian horizontal cells. Therefore horizontal cells were isolated after enzymatical and mechanical dissociation of the adult mouse retina and visually identified. We recorded from horizontal cell bodies using the whole cell and outside-out configuration of the patch-clamp technique. Extracellular application of GABA induced inward currents carried by chloride ions. GABA-evoked currents were completely and reversibly blocked by the competitive GABAA receptor antagonist bicuculline (IC50 = 1.7 μM), indicating expression of GABAA but not GABAC receptors. Their affinity for GABA was moderate (EC50 = 30 μM), and the Hill coefficient was 1.3, corresponding to two GABA binding sites. GABA responses were partially reduced by picrotoxin with differential effects on peak and steady-state current values. Zinc blocked the GABA response with an IC50 value of 7.3 μM in a noncompetitive manner. Furthermore, GABA receptors of horizontal cells were modulated by extracellular application of diazepam, zolpidem, methyl 6,7-dimethoxy-4-ethyl-β-carboxylate, pentobarbital, and alphaxalone, thus showing typical pharmacological properties of CNS GABAA receptors. GABA-evoked single-channel currents were characterized by a main conductance state of 29.8 pS and two subconductance states (20.2 and 10.8 pS, respectively). Kinetic analysis of single-channel events within bursts revealed similar mean open and closed times for the main conductance and the 20.2-pS subconductance state, resulting in open probabilities of 44.6 and 42.7%, respectively. The ratio of open to closed times, however, was significantly different for the 10.8-pS subconductance state with an open probability of 57.2%.

Download Full-text

Synaptic Remodeling in the Cone Pathway After Early Postnatal Horizontal Cell Ablation

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.657594 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lena Nemitz ◽

Karin Dedek ◽

Ulrike Janssen-Bienhold

Keyword(s):

Synapse Formation ◽

Outer Nuclear Layer ◽

Horizontal Cell ◽

Bipolar Cells ◽

Horizontal Cells ◽

Mouse Retina ◽

Retina Development ◽

Synaptic Remodeling ◽

Cell Ablation ◽

Cone Pathway

The first synapse of the visual pathway is formed by photoreceptors, horizontal cells and bipolar cells. While ON bipolar cells invaginate into the photoreceptor terminal and form synaptic triads together with invaginating horizontal cell processes, OFF bipolar cells make flat contacts at the base of the terminal. When horizontal cells are ablated during retina development, no invaginating synapses are formed in rod photoreceptors. However, how cone photoreceptors and their synaptic connections with bipolar cells react to this insult, is unclear so far. To answer this question, we specifically ablated horizontal cells from the developing mouse retina. Following ablation around postnatal day 4 (P4)/P5, cones initially exhibited a normal morphology and formed flat contacts with OFF bipolar cells, but only few invaginating contacts with ON bipolar cells. From P15 on, synaptic remodeling became obvious with clustering of cone terminals and mislocalized cone somata in the OPL. Adult cones (P56) finally displayed highly branched axons with numerous terminals which contained ribbons and vesicular glutamate transporters. Furthermore, type 3a, 3b, and 4 OFF bipolar cell dendrites sprouted into the outer nuclear layer and even expressed glutamate receptors at the base of newly formed cone terminals. These results indicate that cones may be able to form new synapses with OFF bipolar cells in adult mice. In contrast, cone terminals lost their invaginating contacts with ON bipolar cells, highlighting the importance of horizontal cells for synapse maintenance. Taken together, our data demonstrate that early postnatal horizontal cell ablation leads to differential remodeling in the cone pathway: whereas synapses between cones and ON bipolar cells were lost, new putative synapses were established between cones and OFF bipolar cells. These results suggest that synapse formation and maintenance are regulated very differently between flat and invaginating contacts at cone terminals.

Download Full-text

Dopamine Modulates Synaptic Transmission Between Rat Olfactory Bulb Neurons in Culture

Journal of Neurophysiology ◽

10.1152/jn.01058.2002 ◽

2003 ◽

Vol 90 (1) ◽

pp. 395-404 ◽

Cited By ~ 49

Author(s):

Nestor G. Davila ◽

Laura J. Blakemore ◽

Paul Q. Trombley

Keyword(s):

T Cells ◽

Olfactory Bulb ◽

Synaptic Transmission ◽

Calcium Channel ◽

Receptor Agonist ◽

D2 Receptor ◽

D1 Receptor ◽

Dopamine Synthesis ◽

Culture Techniques ◽

Channel Currents

The glomerular layer of the olfactory bulb (OB) contains synaptic connections between olfactory sensory neurons and OB neurons as well as connections among OB neurons. A subpopulation of external tufted cells and periglomerular cells (juxtaglomerular neurons) expresses dopamine, and recent reports suggest that dopamine can inhibit olfactory sensory neuron activation of OB neurons. In this study, whole cell electrophysiological and primary culture techniques were employed to characterize the neuromodulatory properties of dopamine on glutamatergic transmission between rat OB mitral/tufted (M/T) cells and interneurons. Immunocytochemical analysis confirmed the expression of tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, in a subpopulation of cultured neurons. D2 receptor immunoreactivity was also observed in cultured M/T cells. Dopamine reduced spontaneous excitatory synaptic events recorded in interneurons. Although the D1 receptor agonist SKF38393 and the D2 receptor agonist bromocriptine mesylate mimicked this effect, evoked excitatory postsynaptic potentials (EPSPs) recorded from monosynaptically coupled neuron pairs were attenuated by dopamine and bromocriptine but not by SKF38393 . Neither glutamate-evoked currents nor the membrane resistance of the postsynaptic interneuron were affected by dopamine. However, evoked calcium channel currents in the presynaptic M/T cell were diminished during the application of either dopamine or bromocriptine, but not SKF38393 . Dopamine suppressed calcium channel currents even after nifedipine blockade of L-type channels, suggesting that inhibition of the dihydropyridine-resistant high-voltage activated calcium channels implicated in transmitter release may mediate dopamine's effects on spontaneous and evoked synaptic transmission. Together, these data suggest that dopamine inhibits excitatory neurotransmission between M/T cells and interneurons via a presynaptic mechanism.

Download Full-text

Retinal horizontal cells use different synaptic sites for global feedforward and local feedback signaling

10.1101/780031 ◽

2019 ◽

Author(s):

Christian Behrens ◽

Yue Zhang ◽

Shubhash Chandra Yadav ◽

Silke Haverkamp ◽

Stephan Irsen ◽

...

Keyword(s):

Horizontal Cell ◽

Plexiform Layer ◽

Spatial Arrangement ◽

Bipolar Cells ◽

Horizontal Cells ◽

Mouse Retina ◽

Gamma Aminobutyric Acid ◽

Axon Terminals ◽

Specific Feedback ◽

Local Feedback

AbstractIn the outer plexiform layer (OPL) of the mouse retina, two types of cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). This transmission is modulated by a single horizontal cell (HC) type, the only interneuron in the outer retina. Horizontal cells form feedback synapses with cones and feedforward synapses with CBCs. However, the exact computational role of HCs is still debated. Along with performing global signaling within their laterally coupled network, HCs also provide local, cone-specific feedback. Specifically, it has not been clear which synaptic structures HCs use to provide local feedback to cones and global forward signaling to CBCs.Here, we reconstructed in a serial block-face electron microscopy volume the dendritic trees of five HCs as well as cone axon terminals and CBC dendrites to quantitatively analyze their connectivity. In addition to the fine HC dendritic tips invaginating cone axon terminals, we also identified “bulbs”, short segments of increased dendritic diameter on the primary dendrites of HCs. These bulbs are located well below the cone axon terminal base and make contact to other cells mostly identified as other HCs or CBCs. Using immunolabeling we show that HC bulbs express vesicular gamma-aminobutyric acid transporters and co-localize with GABA receptor γ2 subunits. Together, this suggests the existence of two synaptic strata in the mouse OPL, spatially separating cone-specific feedback and feedforward signaling to CBCs. A biophysics-based computational model of a HC dendritic branch supports the hypothesis that the spatial arrangement of synaptic contacts allows simultaneous local feedback and global feedforward signaling.

Download Full-text

Synaptic Scaffolds, Ion Channels and Polyamines in Mouse Photoreceptor Synapses: Anatomy of a Signaling Complex

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.667046 ◽

2021 ◽

Vol 15 ◽

Author(s):

Alejandro Vila ◽

Eyad Shihabeddin ◽

Zhijing Zhang ◽

Abirami Santhanam ◽

Christophe P. Ribelayga ◽

...

Keyword(s):

Ion Channels ◽

Horizontal Cell ◽

Plexiform Layer ◽

Horizontal Cells ◽

Mouse Retina ◽

Pannexin 1 ◽

Signaling Complex ◽

Voltage Dependent ◽

Polyamine Content ◽

And Control

Synaptic signaling complexes are held together by scaffold proteins, each of which is selectively capable of interacting with a number of other proteins. In previous studies of rabbit retina, we found Synapse-Associated Protein-102 (SAP102) and Channel Associated Protein of Synapse-110 (Chapsyn110) selectively localized in the tips of horizontal cell processes at contacts with rod and cone photoreceptors, along with several interacting ion channels. We have examined the equivalent suites of proteins in mouse retina and found similarities and differences. In the mouse retina we identified Chapsyn110 as the scaffold selectively localized in the tips of horizontal cells contacting photoreceptors, with Sap102 more diffusely present. As in rabbit, the inward rectifier potassium channel Kir2.1 was present with Chapsyn110 on the tips of horizontal cell dendrites within photoreceptor invaginations, where it could provide a hyperpolarization-activated current that could contribute to ephaptic signaling in the photoreceptor synapses. Pannexin 1 and Pannexin 2, thought to play a role in ephaptic and/or pH mediated signaling, were present in the outer plexiform layer, but likely not in the horizontal cells. Polyamines regulate many ion channels and control the degree of rectification of Kir2.1 by imposing a voltage-dependent block. During the day polyamine immunolabeling was unexpectedly high in photoreceptor terminals compared to other areas of the retina. This content was significantly lower at night, when polyamine content was predominantly in Müller glia, indicating daily rhythms of polyamine content. Both rod and cone terminals displayed the same rhythm. While polyamine content was not prominent in horizontal cells, if polyamines are released, they may regulate the activity of Kir2.1 channels located in the tips of HCs. The rhythmic change in polyamine content of photoreceptor terminals suggests that a daily rhythm tunes the behavior of suites of ion channels within the photoreceptor synapses.

Download Full-text

Modulation of A-type potassium currents in retinal horizontal cells by extracellular calcium and zinc

Visual Neuroscience ◽

10.1017/s0952523806239993 ◽

2006 ◽

Vol 23 (5) ◽

pp. 825-832 ◽

Cited By ~ 6

Author(s):

DAO-QI ZHANG ◽

ZIYI SUN ◽

DOUGLAS G. MCMAHON

Keyword(s):

Steady State ◽

Potassium Channels ◽

Horizontal Cell ◽

Horizontal Cells ◽

Resting Membrane Potential ◽

Inactivation Curve ◽

Outward Currents ◽

Steady State Inactivation ◽

The Mean ◽

Kinetics Of

Extracellular Ca2+ and Zn2+ influence many aspects of retinal function. Here, we examined the effect of external Ca2+ and Zn2+ on potassium channels of retinal horizontal cells. When extracellular Ca2+ was lowered from 3 mM to 0.3 mM, horizontal cell transient outward currents elicited by voltage steps from resting membrane potential (−70 mV) were decreased by approximately 50%, whereas the sustained currents remained unchanged. This effect was due to a hyperpolarizing shift in the steady-state inactivation curve of A-type K+ currents when extracellular Ca2+ concentration was lowered. The mean half inactivation potential of the steady-state inactivation curves was hyperpolarized from −56.3 ± 4.7 mV in 3 mM Ca2+ to −76.4 ± 3.9 mV in 0.3 mM Ca2+. Neither the state-steady activation curve nor the kinetics of inactivation was significantly changed in low extracellular Ca2+. The addition of 30 μM Zn2+ restored peak outward currents in 0.3 mM Ca2+. The half inactivation voltages were depolarized from −70 ± 2.8 mV in 0.3 mM Ca2+ to −56 ± 2.6 mV in 0.3 mM Ca2+ plus 30 μM Zn2+. Taken together, the results indicate that external Ca2+ and Zn2+ maintain the activity of A-type potassium channels in retinal horizontal cells by influencing the voltage dependence of steady-state inactivation.

Download Full-text