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How neurons in the eye feed signals back to photoreceptors to optimize sensitivity to patterns of light appears mediated by one or more unconventional mechanisms. Via these mechanisms, horizontal cells control synaptic gain and enhance key aspects of temporal and spatial light adaptation, including center-surround receptive field antagonism. After the transduction of light energy into an electrical signal in photoreceptors, a major task in visual processing is transmission of an optimized signal to the follower neurons in the retina. For this to happen, the release of the excitatory neurotransmitter glutamate from photoreceptors is carefully regulated via feedback from horizontal cells, which acts like a thermostat to keep synaptic transmission in an optimal range during changes in light patterns and intensities. A recently described model that casts a classical neurotransmitter system together with ion transport mechanisms to adjust the alkaline milieu outside the synapse, is emphasized here. We review the new evidence showing how this novel inter-neuronal messaging system carries the feedback inhibition using two separate, but interwoven, regulated systems. It may be the complex interplay between these two signaling modalities, creating synaptic modulation-at-a-distance, that has made its definition difficult. The foundations of our understanding of the feedback mechanism from horizontal cells to photoreceptors have been long established: Horizontal cells have broad receptive fields, suitable for providing surround inhibition, their membrane potential regulates inhibition of photoreceptor voltage-gated calcium channels, and strong artificial pH buffering eliminates this action. This report compares and contrasts models of how these foundations are linked, focusing on a recent report of a novel action of GABA in mammals that shows tonic horizontal cell release of GABA activating chloride and bicarbonate permeable GABA autoreceptors. The membrane potential of horizontal cells provides the driving force for GABAR-mediated bicarbonate efflux, alkalinizing the cleft when horizontal cells are hyperpolarized by light or adding to their depolarization cells in darkness by contributing to cleft acidification via NHE-mediated proton efflux. This model reverses interpretations of earlier studies that were considered to rule out a role for GABA in feedback to cones.

Author(s): Crawford, Emily D; Acosta, Irene; Ahyong, Vida; Anderson, Erika C; Arevalo, Shaun; Asarnow, Daniel; Axelrod, Shannon; Ayscue, Patrick; Azimi, Camillia S; Azumaya, Caleigh M; Bachl, Stefanie; Bachmutsky, Iris; Bhaduri, Aparna; Brown, Jeremy Bancroft; Batson, Joshua; Behnert, Astrid; Boileau, Ryan M; Bollam, Saumya R; Bonny, Alain R; Booth, David; Borja, Michael Jerico B; Brown, David; Buie, Bryan; Burnett, Cassandra E; Byrnes, Lauren E; Cabral, Katelyn A; Cabrera, Joana P; Caldera, Saharai; Canales, Gabriela; Castaneda, Gloria R; Chan, Agnes Protacio; Chang, Christopher R; Charles-Orszag, Arthur; Cheung, Carly; Chio, Unseng; Chow, Eric D; Citron, Y Rose; Cohen, Allison; Cohn, Lillian B; Chiu, Charles; Cole, Mitchel A; Conrad, Daniel N; Constantino, Angela; Cote, Andrew; Crayton-Hall, Tre'Jon; Darmanis, Spyros; Detweiler, Angela M; Dial, Rebekah L; Dong, Shen; Duarte, Elias M; Dynerman, David; Egger, Rebecca; Fanton, Alison; Frumm, Stacey M; Fu, Becky Xu Hua; Garcia, Valentina E; Garcia, Julie; Gladkova, Christina; Goldman, Miriam; Gomez-Sjoberg, Rafael; Gordon, M Grace; Grove, James CR; Gupta, Shweta; Haddjeri-Hopkins, Alexis; Hadley, Pierce; Haliburton, John; Hao, Samantha L; Hartoularos, George; Herrera, Nadia; Hilberg, Melissa; Ho, Kit Ying E; Hoppe, Nicholas; Hosseinzadeh, Shayan; Howard, Conor J; Hussmann, Jeffrey A; Hwang, Elizabeth; Ingebrigtsen, Danielle; Jackson, Julia R; Jowhar, Ziad M; Kain, Danielle; Kim, James YS; Kistler, Amy; Kreutzfeld, Oriana; Kulsuptrakul, Jessie; Kung, Andrew F

The stream of visual information sent from photoreceptors to second-order bipolar cells is intercepted by laterally interacting horizontal cells that generate feedback to optimize and improve the efficiency of signal transmission. The mechanisms underlying the regulation of graded photoreceptor synaptic output in this nonspiking network have remained elusive. Here, we analyze with patch clamp recording the novel mechanisms by which horizontal cells control pH in the synaptic cleft to modulate photoreceptor neurotransmitter release. First, we show that mammalian horizontal cells respond to their own GABA release and that the results of this autaptic action affect cone voltage-gated Ca2+ channel (CaV channel) gating through changes in pH. As a proof-of-principle, we demonstrate that chemogenetic manipulation of horizontal cells with exogenous anion channel expression mimics GABA-mediated cone CaV channel inhibition. Activation of these GABA receptor anion channels can depolarize horizontal cells and increase cleft acidity via Na+/H+ exchanger (NHE) proton extrusion, which results in inhibition of cone CaV channels. This action is effectively counteracted when horizontal cells are sufficiently hyperpolarized by increased GABA receptor (GABAR)-mediated HCO3- efflux, alkalinizing the cleft and disinhibiting cone CaV channels. This demonstrates how hybrid actions of GABA operate in parallel to effect voltage-dependent pH changes, a novel mechanism for regulating synaptic output.

Outdoor air pollution is a major environmental health problem throughout the world. In particular, exposure to particulate matter (PM) has been associated with the development and exacerbation of several respiratory diseases, including asthma. Although the adverse health effects of PM have been demonstrated for many years, the underlying mechanisms have not been fully identified. In this review, we focus on the role of the lung epithelium and specifically highlight multiple cytokines in PM-induced respiratory responses. We describe the available literature on the topic including in vitro studies, findings in humans (ie observations in human cohorts, human controlled exposure and ex vivo studies) and in vivo animal studies. In brief, it has been shown that exposure to PM modulates the airway epithelium and promotes the production of several cytokines, including IL-1, IL-6, IL-8, IL-25, IL-33, TNF-α, TSLP and GM-CSF. Further, we propose that PM-induced type 2-promoting cytokines are important mediators in the acute and aggravating effects of PM on airway inflammation. Targeting these cytokines could therefore be a new approach in the treatment of asthma.

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 ICaby 24%. The D1R antagonist SCH23390 (20 μM) reduced dopamine and SKF38393 inhibition. Dopamine slowed ICaactivation, blocking ICaby 38% early in a voltage step. Enhanced early inhibition of ICawas eliminated by applying voltage prepulses to +120 mV for 100 ms, increasing ICaby 31% and 11% for early and steady-state currents, respectively. Voltage-dependent facilitation of ICaand 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, ICawas smaller and showed the same slowed kinetics seen during D1R activation. With GTPγS in the pipette, additional block of ICaby dopamine was only 6%. Strong depolarizing voltage prepulses restored the GTPγS-reduced early ICaamplitude by 36% and steady-state ICaamplitude by 3%. These results suggest that dopaminergic inhibition of ICavia D1Rs is primarily mediated through the action of Gβγ proteins in horizontal cells.

Whilst the performance of small THGEMs is well known, here we consider the challenges in scaling these up to large area charge readouts. We first verify the expected gain of larger THGEMs by reporting experimental Townsend coefficients for a 10 cm diameter THGEM in low-pressure CF$_4$. Large area 50 cm by 50 cm THGEMs were sourced from a commercial PCB supplier and geometrical imperfections were observed which we quantified using an optical camera setup. The large area THGEMs were experimentally characterised at Boulby Underground Laboratory through a series of gain calibrations and alpha spectrum measurements. ANSYS, Magboltz and Garfield++ simulations of the design of a TPC based on the large area THGEMs are presented. We also consider their implications for directional dark matter research and potential applications within nuclear security., Comment: 18 pages, 22 figures

The cellular mechanisms underlying feedback signaling from horizontal cells to photoreceptors, important for formation of receptive field surrounds of early visual neurons, remain unsettled. Mammalian horizontal cells express a complement of synaptic proteins that are necessary and sufficient for calcium-dependent exocytosis of inhibitory neurotransmitters at their contacts with photoreceptor terminals, suggesting that they are capable of releasing GABA via vesicular release. To test if horizontal cell vesicular release is involved in feedback signaling, we perturbed inhibitory neurotransmission in these cells by targeted deletion of the vesicular GABA transporter (VGAT), the protein responsible for uptake of inhibitory transmitter by synaptic vesicles. To manipulate horizontal cells selectively, an iCre mouse line with Cre recombinase expression controlled by connexin57 (Cx57) regulatory elements was generated. In Cx57-iCre mouse retina, only horizontal cells expressed Cre protein and its expression occurred in all retinal regions. After crossing with a VGATflox/flox mouse line, VGAT was selectively eliminated from horizontal cells, which was confirmed immunohistochemically. Voltage-gated ion channel currents in horizontal cells of Cx57-VGAT -/- mice were the same as Cx57-VGAT+/+ controls, as were the cells’ responses to the ionotropic glutamate receptor agonist, kainate, but the response to the GABAA receptor agonist, muscimol, in Cx57-VGAT -/- mice was larger. In contrast, feedback inhibition of photoreceptor calcium channels, which in control animals is induced by horizontal cell depolarization, was completely absent in Cx57-VGAT -/- mice. The results suggest that vesicular release of GABA from horizontal cells is required for feedback inhibition of photoreceptors. Significance Statement: Feedback inhibition by horizontal cells regulates the photoreceptor calcium channels responsible for the release of the neurotransmitter, glutamate. This feedback inhibition contributes to the formation of the receptive field surrounds of early visual neurons, important for contrast sensitivity and color opponency in vision. The cellular mechanisms underlying feedback inhibition are not fully understood. One disputed mechanism for mammalian horizontal cell inhibitory output involves the vesicular release of the inhibitory neurotransmitter, GABA. By deleting selectively the transporter that normally loads GABA into vesicles in horizontal cells, we show that horizontal cells lose their ability to modulate photoreceptor calcium signals. These findings implicate a role for the vesicular release of GABA in mediating inhibitory feedback.

Ion-thinned longitudinal sections of a third molar were observed by bright- and dark-field electron microscopy. In bright field, the hydroxyapatite crystallites in enamel appeared as long rods, but, when observed in dark field, the crystallites were rectangular, with a mean length of 321 A.