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Section of peripheral retina stained for glutamate. Note strongly labelled rod spherules (small arrows) and moderately labelled cone pedicles (large arrows). These terminals are more strongly labelled than their corresponding inner segments, and outer segments of rods are more strongly labelled than those of cones (asterisk). Star denotes one of several cells in the INL (bipolar or Muller cell) that failed to stain for glutamate (identified as cell by narrowing the condenser aperture). Abbreviations as in Figure 1. Bar = 20 pm.
Source publication
The distribution of the neuroactive amino acids glutamate, GABA, and glycine in the human retina was examined in consecutive semithin sections treated with antisera specific for fixed glutamate, GABA, and glycine, respectively.
Glutamate immunoreactivity was conspicuous in all photoreceptor cells (rods more strongly labelled than cones), and in a m...
Contexts in source publication
Context 1
... staining occurred in most (more than 83%, see Table 1) of the cells in the ganglion cell layer (perikarya and dendrites), and in axons in the nerve fibre layer. Staining of the same intensity was seen in the perikarya and processes of many presumed bipolar cells, and in what appeared to be rod terminal spherules in the outer plexiform layer (Fig. 3). The inner plexiform layer also contained strongly immunoreactive structures (as well as many moderately immunoreactive), probably representing ganglion cell dendrites (see Fig. 1A) and, possibly, bipolar and amacrine cell terminals. In the perifoveal region, occasional strongly immunopositive cells (similar to ganglion cells in size, ...
Context 2
... '86) as well as radiolabelled glutamate (Bruun and Ehinger, '74; Brandon and Lam, '83; Sarthy et al., '86) accumulate to a higher concentration in rods than in cones. The immunostaining pattern in the present material indicates that the level of glutamate is higher in the receptor terminals than in the receptor perikarya and inner segments (e.g., Fig. 3). The existence of such an intracellular glutamate gradient has also been demonstrated in the well-characterized glutamatergic cells of the hippocampus (Bramham et al., '90) and represents strong support for a transmitter role of ...
Citations
... Overall, the "vertical" signal transmission from photoreceptors to bipolar cells and ganglion cells is mainly glutamatergic, but there is substantial modification of transmission by lateral interneurons, namely, horizontal cells (which modulate transmission between photoreceptors and bipolar cells) and many types of amacrine cells (mediating transmission between bipolar cells and modifying transmission from bipolar to ganglion cells). Many of these lateral interactions comprise GABAergic inhibition (Yazulla, 1986;Davanger et al., 1991;Yang, 2004). Hence, if E-I alterations in individuals with ASD are generalized across the central nervous system, they may also manifest as functional changes in the retina assessed using the ERG, especially in responses (a-and b-wave) to single flashes as they capture the vertical glutamate pathway from photoreceptors to bipolar cells, and this transmission is expected to be modulated by GABAergic horizontal cells. ...
Alterations in γ-aminobutyric acid (GABA) have been implicated in sensory differences in individuals with autism spectrum disorder (ASD). Visual signals are initially processed in the retina, and in this study, we explored the hypotheses that the GABA-dependent retinal response to light is altered in individuals with ASD. Light-adapted electroretinograms were recorded from 61 adults (38 males and 23 females; n = 22 ASD) in response to three stimulus protocols: (1) the standard white flash, (2) the standard 30 Hz flickering protocol, and (3) the photopic negative response protocol. Participants were administered an oral dose of placebo, 15 or 30 mg of arbaclofen (STX209, GABA B agonist) in a randomized, double-blind, crossover order before the test. At baseline (placebo), the a-wave amplitudes in response to single white flashes were more prominent in ASD, relative to typically developed (TD) participants. Arbaclofen was associated with a decrease in the a-wave amplitude in ASD, but an increase in TD, eliminating the group difference observed at baseline. The extent of this arbaclofen-elicited shift significantly correlated with the arbaclofen-elicited shift in cortical responses to auditory stimuli as measured by using an electroencephalogram in our prior study and with broader autistic traits measured with the autism quotient across the whole cohort. Hence, GABA-dependent differences in retinal light processing in ASD appear to be an accessible component of a wider autistic difference in the central processing of sensory information, which may be upstream of more complex autistic phenotypes.
... As noted above, GABA released by amacrine cells and RGCs is an important regulator of inner retinal development [7,[203][204][205][206][207][208]. GABAB receptors are metabotropic G protein-coupled receptors on amacrine cells and RGCs, where they are capable of inducing neuronal hyperpolarization through the opening of G protein-gated inwardly rectifying K + channels and of inhibiting neurotransmitter release by inhibiting voltage-gated Ca 2+ channels both pre-and post-synaptically [115]. ...
The intricate functionality of the vertebrate retina relies on the interplay between neurotransmitter activity and calcium (Ca2+) dynamics, offering important insights into developmental processes, physiological functioning, and disease progression. Neurotransmitters orchestrate cellular processes to shape the behavior of the retina under diverse circumstances. Despite research to elucidate the roles of individual neurotransmitters in the visual system, there remains a gap in our understanding of the holistic integration of their interplay with Ca2+ dynamics in the broader context of neuronal development, health, and disease. To address this gap, the present review explores the mechanisms used by the neurotransmitters glutamate, gamma-aminobutyric acid (GABA), glycine, dopamine, and acetylcholine (ACh) and their interplay with Ca2+ dynamics. This conceptual outline is intended to inform and guide future research, underpinning novel therapeutic avenues for retinal-associated disorders.
... Therefore, we postulated the following hypothesis (Figure 9). The ON and OFF pathways in the normal retina consist of cone and rod pathways (Davanger et al., 1991;Wettschureck and Offermanns, 2005;Volgyi et al., 2013;Fain and Sampath, 2018). In the cone pathway, cone photoreceptors synapse with ON cone bipolar cells (ON CBCs) and OFF cone bipolar cells (OFF CBCs). ...
One of the critical prerequisites for the successful development of retinal prostheses is understanding the physiological features of retinal ganglion cells (RGCs) in the different stages of retinal degeneration (RD). This study used our custom-made rd10 mice, C57BL/6-Pde6bem1(R560C)Dkl/Korl mutated on the Pde6b gene in C57BL/6J mouse with the CRISPR/Cas9-based gene-editing method. We selected the postnatal day (P) 45, P70, P140, and P238 as representative ages for RD stages. The optomotor response measured the visual acuity across degeneration stages. At P45, the rd10 mice exhibited lower visual acuity than wild-type (WT) mice. At P140 and older, no optomotor response was observed. We classified RGC responses to the flashed light into ON, OFF, and ON/OFF RGCs via in vitro multichannel recording. With degeneration, the number of RGCs responding to the light stimulation decreased in all three types of RGCs. The OFF response disappeared faster than the ON response with older postnatal ages. We elicited RGC spikes with electrical stimulation and analyzed the network-mediated RGC response in the rd10 mice. Across all postnatal ages, the spikes of rd10 RGCs were less elicited by pulse amplitude modulation than in WT RGCs. The ratio of RGCs showing multiple peaks of spike burst increased in older ages. The electrically evoked RGC spikes by the pulse amplitude modulation differ across postnatal ages. Therefore, degeneration stage-dependent stimulation strategies should be considered for developing retinal prosthesis and successful vision restoration.
... The RNFL superior quadrant and total RNFL values measured for both eyes were thinner in patients compared to that in healthy controls. When examined along with the common neurotransmitter hypothesis, it was shown that GABA, glutamate, and glycine, which play roles in addiction, were found in human visual pathways and retinal layers (24) . It was found in an animal study that glutamate levels changed in the retina after ischemia (25) . ...
Purpose:
This study aimed to examine optical coherence tomography findings in patients with opiate use disorder by comparing them with healthy controls.
Methods:
The study included 30 opiate use disorder patients and 30 controls. The participants' detailed biomicroscopic examinations, visual acuity, intraocular pressure, and both eye examinations were evaluated. A total of 120 eyes were evaluated using optical coherence tomography, measuring the central macular thickness, mean macular thickness, mean macular volume and retinal nerve fiber layer thickness. Moreover, all participants filled in the demographic data form and Barratt Impulsiveness Scale.
Results:
Upon examination of the optical coherence tomography findings, central macular thickness, mean macular thickness, and mean macular volume were thinner in both eyes in patients with opiate use disorder (p<0.01 in all measurements in both eyes). Similarly, the total values of the superior quadrant and retinal nerve fiber layer thickness were statistically significant in both eyes compared to that in the control group (p=0.007, p=0.002; p=0.049, p=0.007, in the right and left eyes, respectively). Only the left eye was positively correlated with retinal nerve fiber layer superior quadrant measurement and hospitalization (r=0.380, p=0.039).
Conclusion:
Our results revealed that the patients' central macular thickness, mean macular thickness, and mean macular volume values were thinner. Increase in the retinal nerve fiber layer thickness superior quadrant thickness and total value was also observed. Further studies with larger sampling groups that evaluate neuroimaging findings should be conducted.
... In addition to these classical amacrine neurons, a small set of inhibitory interplexiform amacrine neurons extend their dendritic processes to both, the inner and outer plexiform layer, providing a feedback loop to transmit information from the inner to the outer retina. It had been reported that glycinergic and GABA amacrine neurons in the mammalian retina comprise about 35-40% and 40-50%, respectively (7)(8)(9)(10). These inhibitory neurons together modulate the message delivered to the ganglion cells. ...
... After analyzing the localization and quantity of cells with both markers, we identified a consistent 8-10% of ACs expressing both markers, GAD67 and GlyT1, providing additional evidence of the presence of dual -glycinergic/GABAergic population of neurons (Fig. 5B). Consistent with our findings in the mouse retina, the presence of subpopulations of GlyT1/GAD65 or GABA/glycine containing neurons have been reported in the human, macaque and marmoset retinas, accounting for 3-10% of the total inhibitory ACs (8,(66)(67)(68). Given that the majority of studies characterizing the glycinergic and GABAergic amacrine neurons have been performed with anti-GAD or anti-GAT antibodies, we took the advantage of available transgenic lines expressing reporter genes in GABA neurons. ...
... These studies support the co-release of both GABA and glycine from a single presynaptic AC neuron onto a single postsynaptic neuron and the presence of dual GABA/glycine amacrine neurons. This hypothesis is supported by the co-localization of the amino acids glycine and GABA in the same amacrine neurons in the primate retina, accounting for 3-4% of the amacrine cells in those studies (8,67). Additional evidence come from the detection of GABA and Glycine receptors onto a single neighbor AC neuron (88) or ganglion cells in the mouse and rat retina (86,87). ...
The amacrine neurons in the mammalian retina comprise a large variety of cell types with distinct properties and functions that serve to integrate and modulate signals presented to output neurons. The majority of them use either glycine or GABA as inhibitory neurotransmitters and express the glycine transporter 1 (GlyT1) or glutamic acid decarboxylase (GAD67) and GABA transporters (GAT1 and GAT3), as a glycinergic or GABAergic marker respectively. We report here a novel subpopulation of amacrine neurons expressing both, GABAergic and glycinergic markers, in retinas from wild-type C57BL/6J mice and two transgenic lines. In retinal sections from the transgenic line expressing eGFP under the control of the glycine transporter 2, eGFP expression was exclusively found in cell bodies and dendrites of inhibitory amacrine neurons, identified for their immunoreactivity to syntaxin 1A. All of the glycinergic and a large portion of the GABAergic amacrine neurons contained eGFP; of these, 8-10% of GlyT1 positive neurons were also labeled either with GAD67, GAT1 or GAT3. These findings were confirmed in retinas from a wild-type and a mouse line expressing eGFP under the GAD67 promoter and two different anti-GlyT1 antibodies, showing the presence of a subpopulation with a dual phenotype. Moreover, eGFP-positive dendrites on both mouse lines were found juxtaposed to GlyR subunits and the scaffold protein gephyrin in several areas of the inner plexiform layer, demonstrating the glycinergic character of these neurons. This dual phenotype was also demonstrated in primary retina cultures, in which isolated neurons were positive for GlyT1 and GAD67 or GAT1/3. Altogether, these data provide compelling evidence of a subpopulation of dual inhibitory, glycinergic/GABAergic amacrine neurons. The co-release of both neurotransmitters may serve to strengthen the inhibition on ganglion cells under synaptic hyperexcitability.
... Over 25 morphological types of amacrine cell were classified in Golgi preparations of macaque (Mariani, 1990) and human retinas but in total there may be as many as 30 to 60 morphological types, depending on how a type is defined. Immunohistochemical studies suggest that about half of the amacrine population uses GABA and the other half uses glycine as their neurotransmitter (Marc and Liu, 1985;Hendrickson et al., 1988;Grünert and Wässle, 1990;Davanger et al., 1991;Crooks and Kolb, 1992;Martin and Grünert, 1992;Koontz et al., 1993;Kalloniatis et al., 1996;Weltzien et al., 2015). Small numbers of amacrine cells expressing both GABA and glycine immunoreactivity, as well as cells expressing neither GABA nor glycine have also been reported (Martin and Grünert, 1992;Kalloniatis et al., 1996;Weltzien et al., 2015). ...
This review summarises our current knowledge of primate including human retina focusing on bipolar, amacrine and ganglion cells and their connectivity. We have two main motivations in writing. Firstly, recent progress in non-invasive imaging methods to study retinal diseases mean that better understanding of the primate retina is becoming an important goal both for basic and for clinical sciences. Secondly, genetically modified mice are increasingly used as animal models for human retinal diseases. Thus, it is important to understand to which extent the retinas of primates and rodents are comparable. We first compare cell populations in primate and rodent retinas, with emphasis on how the fovea (despite its small size) dominates the neural landscape of primate retina. We next summarise what is known, and what is not known, about the postreceptoral neurone populations in primate retina. The inventories of bipolar and ganglion cells in primates are now nearing completion, comprising ∼12 types of bipolar cell and at least 17 types of ganglion cell. Primate ganglion cells show clear differences in dendritic field size across the retina, and their morphology differs clearly from that of mouse retinal ganglion cells. Compared to bipolar and ganglion cells, amacrine cells show even higher morphological diversity: they could comprise over 40 types. Many amacrine types appear conserved between primates and mice, but functions of only a few types are understood in any primate or non-primate retina. Amacrine cells appear as the final frontier for retinal research in monkeys and mice alike.
... The neurotransmitter spectrum of RGCs is, in large part, unknown due to many reasons. RGCs have been verified to be immunoreactive to glutamate by many studies with its positive signals in the cell bodies (Crooks and Kolb, 1992;Davanger et al., 1991;Jojich and Pourcho, 1996;Kalloniatis and Fletcher, 1993;Sun and Crossland, 2000) as well as axon terminals (Beaudet et al., 1981;Ehinger, 1981;Mize and Butler, 1996;Montero, 1994;Ortega et al., 1995). These observations have strengthened the indication of glutamate excitotoxicity-mediated mechanism of glaucoma, despite the fact that the exact role of glutamate signaling in RGCs is still elusive. ...
The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, arachidonic acid content of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.
... Colocalization of the glutamate and GABA was reported in the hindbrain of frogs (Reichenberger et al., 1997) and lampreys (Villar-Cervino et al., 2011). It was also seen in the visual system of salamanders (Yang, 1996), cats (Jojich and Pourcho, 1996), and humans (Davanger et al., 1991). In the present study both physiological and anatomical findings concur to support the presence of descending MLR glutamatergic projections to RS neurons as shown in lampreys Le Ray et al., 2003). ...
In vertebrates, stimulation of the Mesencephalic Locomotor Region (MLR) on one side evokes symmetrical locomotor movements on both sides. How this occurs was previously examined in detail in a swimmer using body undulations (lamprey), but in tetrapods the downstream projections from the MLR to brainstem neurons remained largely unknown. Here, we examined the brainstem circuits from the MLR to identified reticulospinal neurons in the salamander Notophthalmus viridescens. Using neural tracing, we show that the MLR sends bilateral projections to the middle Reticular Nucleus (mRN, rostral hindbrain) and the inferior Reticular Nucleus (iRN, caudal hindbrain). Ca2+ imaging coupled to electrophysiology in in vitro isolated brains revealed very similar responses in reticulospinal neurons on both sides to a unilateral MLR stimulation. As the strength of MLR stimulation was increased, the responses increased in size in reticulospinal neurons of the mRN and iRN, but the responses in the iRN were smaller. Bath-application or local microinjections of glutamatergic antagonists markedly reduced reticulospinal neuron responses, indicating that the MLR sends glutamatergic inputs to reticulospinal neurons. In addition, reticulospinal cells responded to glutamate microinjections and the size of the responses paralleled the amount of glutamate microinjected. Immunofluorescence coupled with anatomical tracing confirmed the presence of glutamatergic projections from the MLR to reticulospinal neurons. Overall, we show that the brainstem circuits activated by the MLR in the salamander are organized similarly to those previously described in lampreys, indicating that the anatomo-physiological features of the locomotor drive are well conserved in vertebrates.
... It is well established that in mammalian retinas including human the amacrine population can be broadly subdivided into GABAergic and glycinergic cells (Davanger et al., 1991;Crooks and Kolb, 1992;Kalloniatis et al., 1996), whereas displaced amacrine cells are considered GABAergic (W€ assle et al., 1990). In the present study we identified a low proportion of calretinin-positive GABAergic amacrine cells in the inner nuclear layer and a low proportion of the DiI-filled cells in the inner nuclear layer show widefield morphology. ...
Antibodies against calretinin are markers for one type of rod pathway interneurone (AII amacrine cell) in the retina of some but not all mammalian species. The AII cells play a crucial role in night-time (scotopic) vision and have been proposed as a target for optogenetic restoration of vision in retinal disease. In the present study we aimed to characterize the AII cells in human retina. Post mortem human donor eyes were obtained with ethical approval and processed for calretinin immunofluorescence. Calretinin positive somas in the inner nuclear and the ganglion cell layer were filled with the lipophilic dye DiI. The large majority (over 80%) of calretinin immunoreactive cells is located in the inner nuclear layer, is immunopositive for glycine transporter 1 and shows the typical morphology of AII amacrine cells. In addition a small proportion of calretinin positive cells in the inner nuclear layer and in the ganglion cell layer is glutamic acid decarboxylase positive and shows the morphology of wide-field amacrine cells (stellate, semilunar, and thorny amacrine cells). About half of the calretinin cells in the ganglion cell layer are bistratified ganglion cells resembling the small bistratified (presumed blue-ON/yellow-OFF) and the G17 ganglion cell previously described in primates. We conclude that in human retina, antibodies against calretinin can be used to identify AII amacrine cells in the inner nuclear layer as well as wide-field amacrine and small bistratified ganglion cells in the ganglion cell layer. This article is protected by copyright. All rights reserved.
© 2015 Wiley Periodicals, Inc.
... GABA is localized in neonatal rat optic nerve glia, with expression down-regulated with maturation (Ochi et al., 1993;Sakatani et al., 1992), although this may be due to increased rates of GABA degradation since numerous GABA1 WM astrocytes are apparent in adult rat following inhibition of the catabolic enzyme GABA-alpha-ketoglutaric acid aminotransferase (Bull and Blomqvist, 1991). High concentrations of neurotransmitter such as GABA and glycine are also present in a sub-population of mature WM axons in several species (Carlton et al., 1996;Davanger et al., 1991;Rogers and Pow, 1995;Todd and Sullivan, 1990;van den Pol and Gorcs, 1988;Wilson et al., 1996). ...
White matter (WM) tracts are bundles of myelinated axons that provide for rapid communication throughout the CNS and integration in grey matter (GM). The main cells in myelinated tracts are oligodendrocytes and astrocytes, with small populations of microglia and oligodendrocyte precursor cells. The prominence of neurotransmitter signaling in WM, which largely exclude neuronal cell bodies, indicates it must have physiological functions other than neuron-to-neuron communication. A surprising aspect is the diversity of neurotransmitter signaling in WM, with evidence for glutamatergic, purinergic (ATP and adenosine), GABAergic, glycinergic, adrenergic, cholinergic, dopaminergic and serotonergic signaling, acting via a wide range of ionotropic and metabotropic receptors. Both axons and glia are potential sources of neurotransmitters and may express the respective receptors. The physiological functions of neurotransmitter signaling in WM are subject to debate, but glutamate and ATP-mediated signaling have been shown to evoke Ca2+ signals in glia and modulate axonal conduction. Experimental findings support a model of neurotransmitters being released from axons during action potential propagation acting on glial receptors to regulate the homeostatic functions of astrocytes and myelination by oligodendrocytes. Astrocytes also release neurotransmitters, which act on axonal receptors to strengthen action potential propagation, maintaining signaling along potentially long axon tracts. The co-existence of multiple neurotransmitters in WM tracts suggests they may have diverse functions that are important for information processing. Furthermore, the neurotransmitter signaling phenomena described in WM most likely apply to myelinated axons of the cerebral cortex and GM areas, where they are doubtless important for higher cognitive function. GLIA 2014;00:000–000
