Localization of ionotropic glutamate receptors to invaginating dendrites at the cone synapse in primate retina

2005 ◽  
Vol 22 (4) ◽  
pp. 469-477 ◽  
Author(s):  
DAVID J. CALKINS
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Glutamate Release ◽  
Ultrastructural Localization ◽  
Bipolar Cells ◽  
Ionotropic Glutamate Receptors ◽  
Metabotropic Glutamate ◽  
Signal Light ◽  
G Protein Coupled ◽  
Microscopic Distribution

The separation of OFF pathways that signal light decrements from ON pathways that signal light increments occurs at the first retinal synapse. The dendrites of OFF bipolar cells abut the cone pedicle at basal positions distal to the site of glutamate release and express ligand-gated or ionotropic glutamate receptors (GluR). The dendrites of ON bipolar cells penetrate narrow invaginations of the cone pedicle proximal to the site of release and express the G-protein-coupled, metabotropic glutamate receptor, mGluR6. However, recent studies demonstrating the expression of GluR subunits in the rodent rod bipolar cell, known to yield an ON response to light, call this basic segregation of receptors into question. The light-microscopic distribution of many glutamate receptors in the primate retina is now well established. We reexamined their ultrastructural localization in the outer retina ofMacaca fascicularisto test systematically whether invaginating dendrites at the cone synapse, presumably from ON bipolar cells, also express one or more ionotropic subunits. Using preembedding immunocytochemistry for electron microscopy, we quantified the distribution of the AMPA-sensitive subunits GluR2/3 and GluR4 and of the kainate-sensitive subunits GluR6/7 across 207 labeled dendrites occupying specific morphological loci at the cone pedicle. We report, in agreement with published investigations, that the majority of labeled processes for GluR2/3 (70%) and GluR4 (67%) either occupy basal positions or arise from horizontal cells. For GluR6/7, we find a significantly lower fraction of labeled processes at these positions (47%). We also find a considerable number of labeled dendrites for GluR2/3 (10%), GluR4 (21%), and GluR6/7 (18%) at invaginating positions. Surprisingly, for each subunit, the remainder of labeled processes corresponds to “fingers” of presynaptic cytoplasm within the cone invagination.

Are there ionotropic glutamate receptors on the rod bipolar cell of the mouse retina?

1997 ◽  
Vol 14 (1) ◽  
pp. 103-109 ◽  
Author(s):  
Thomas E. Hughes
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Bipolar Cell ◽  
Metabotropic Glutamate Receptor ◽  
Bipolar Cells ◽  
Ionotropic Glutamate Receptors ◽  
Mouse Retina ◽  
Rod Photoreceptor ◽  
Metabotropic Glutamate ◽  
C Terminus

AbstractThere is some evidence that the mammalian rod bipolar cell expresses ionotropic glutamate receptors. This is surprising in light of the strong evidence that the glutamate released by the rod photoreceptor acts upon a metabotropic glutamate receptor-mGluRo-present in the dendrites of the rod bipolar cell. To reexamine the issue of which glutamate receptor subunits may be present on the rod bipolar cell, an immunohistochemical study of acutely dissociated retinal cells was undertaken. Two monoclonal antibodies provided some evidence that GluR2 and/or GluR4, as well as NMDAR1 subunit, are present on the rod bipolar cell. A monoclonal antibody directed against the N-terminus of GluR2 labeled the rod bipolar cells, but two antisera directed against the C-terminus of the same subunit did not. One possible explanation for this discrepancy could be that the rare splice variant GluR2-long, which is endowed with a different C-terminus, could be expressed by the rod bipolar cell. To explore this possibility, RT-PCR was used to amplify the transcripts encoding GluR2 in the neural retina. This revealed that GluR2-long transcripts, with the flop exon, are present.

scholarly journals The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment—A Narrative Review

2021 ◽  
Vol 10 (7) ◽  
pp. 1475
Author(s):  
Waldemar Kryszkowski ◽  
Tomasz Boczek
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Glutamate Release ◽  
Molecular Targets ◽  
Brain Regions ◽  
Psychotic Symptoms ◽  
Unknown Etiology ◽  
Metabotropic Glutamate ◽  
G Protein Coupled

Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology.

scholarly journals Disinhibitory recruitment of NMDA receptor pathways in retina

2014 ◽  
Vol 112 (1) ◽  
pp. 193-203 ◽  
Author(s):  
Santhosh Sethuramanujam ◽  
Malcolm M. Slaughter
Keyword(s):  
Nmda Receptor ◽  
Glutamate Receptors ◽  
Presynaptic Inhibition ◽  
Amacrine Cell ◽  
Glutamate Release ◽  
Relative Strength ◽  
Bipolar Cells ◽  
Ionotropic Glutamate Receptors ◽  
Nmdar Activation ◽  
On And Off Pathways

Glutamate release at bipolar to ganglion cell synapses activates NMDA and AMPA/kainic acid (KA) ionotropic glutamate receptors. Their relative strength determines the output signals of the retina. We found that this balance is tightly regulated by presynaptic inhibition that preferentially suppresses NMDA receptor (NMDAR) activation. In transient ON-OFF neurons, block of GABA and glycine feedback enhanced total NMDAR charge by 35-fold in the ON response and 9-fold in the OFF compared with a 1.7-fold enhancement of AMPA/KA receptors. Blocking only glycine receptors enhanced the NMDAR excitatory postsynaptic current 10-fold in the ON and 2-fold in the OFF pathway. Blocking GABAA or GABAC receptors (GABACRs or GABAARs) produced small changes in total NMDAR charge. When both GABAARs and GABACRs were blocked, the total NMDAR charge increased ninefold in the ON and fivefold in the OFF pathway. This exposed a strong GABACR feedback to bipolar cells that was suppressed by serial amacrine cell synapses mediated by GABAARs. The results indicate that NMDAR currents are large but latent, held in check by dual GABA and glycine presynaptic inhibition. One example of this controlled NMDAR activation is the cross talk between ON and OFF pathways. Blocking the ON pathway increased NMDAR relative strength in the OFF pathway. Stimulus prolongation similarly increased the NMDAR relative strength in the OFF response. This NMDAR enhancement was produced by a diminution in GABA and glycine feedback. Thus the retinal network recruits NMDAR pathways through presynaptic disinhibition.

scholarly journals LRIT3 is required for nyctalopin expression and normal ON and OFF pathway signaling in the retina

2018 ◽  
Author(s):  
Nazarul Hasan ◽  
Gobinda Pangeni ◽  
Thomas A. Ray ◽  
Kathryn M. Fransen ◽  
Jennifer Noel ◽  
...  
Keyword(s):  
Visual Function ◽  
Metabotropic Glutamate Receptor ◽  
Glutamate Release ◽  
Electrode Array ◽  
Light Response ◽  
Photoreceptor Cells ◽  
Sole Source ◽  
Bipolar Cells ◽  
Metabotropic Glutamate ◽  
And Function

ABSTRACTAt its first synapse, the retina establishes two parallel channels that encode light increments (ON) or decrements (OFF). At the same synapse, changes in photoreceptor glutamate release are sensed by ON bipolar cells (BCs) via the metabotropic glutamate receptor 6 (mGluR6), and OFF BCs via ionotropic BCs, which differ in their synaptic configuration with the photoreceptor terminal. ON BCs form invaginating synapses that bring them in close proximity to presynaptic ribbons and the presumed sole source of glutamate release. OFF bipolar cells form flat contacts distal to the ribbon synapse. We investigated the role of LRIT3 in normal assembly and function of the mGlur6 signaling cascade present in ON BCs. We demonstrate that LRIT3 is required for nyctalopin expression and thus TRPM1 expression and function. Using glutamate imaging, whole-cell electrophysiology, and multi-electrode array extracellular recordings we demonstrate that the loss of LRIT3 impacts both the ON and OFF pathways at the level of the BCs. The effect on ON pathway signaling, a lack of ON BC response, is shared by mutants lacking mGluR6, TRPM1 GPR179 or nyctalopin. The effects on the OFF pathway are unique to LRIT3, and include a decrease in response amplitude of both OFF BC and GCs. Based on these results, we propose a working model where LRIT3 is required for either efficient glutamate release or reuptake from the first retinal synapse.SIGNIFICANCE STATEMENTAt the first visual synapse, photoreceptor cells signal to two distinct bipolar cell (BC) populations, one characterized by a depolarizing response to light onset (ON or DBCs), the other by a hyperpolarizing response (OFF or HBCs). The DBC light response depends on a G protein-coupled receptor and associated protein complex, known as the signalplex. Mutations in signalplex proteins lead to DBC pathway-specific loss of visual function. Here we show how loss of LRIT3, a previously identified signalplex protein, prevents functional assembly of the DBC signalplex and alters visual function in both ON and OFF signaling pathways. Thus, our results indicate that the function of LRIT3 at this first synapse extends beyond assembly of the DBC signalplex.

Olfactory Nerve Stimulation-Evoked mGluR1 Slow Potentials, Oscillations, and Calcium Signaling in Mouse Olfactory Bulb Mitral Cells

2006 ◽  
Vol 95 (5) ◽  
pp. 3097-3104 ◽  
Author(s):  
Q. Yuan ◽  
T. Knöpfel
Keyword(s):  
Glutamate Receptors ◽  
High Frequency ◽  
Metabotropic Glutamate Receptor ◽  
Olfactory Nerve ◽  
Ionotropic Glutamate Receptors ◽  
Mitral Cells ◽  
Slow Potential ◽  
Metabotropic Glutamate ◽  
Metabotropic Glutamate Receptor 1 ◽  
Intracellular Ca

Fast synaptic transmission between olfactory receptor neurons and mitral cells (MCs) is mediated through AMPA and NMDA ionotropic glutamate receptors. MCs also express high levels of metabotropic glutamate receptor 1 (mGluR1) whose functional significance is less understood. Here we characterized a slow mGluR1-mediated potential that was evoked by high-frequency (100-Hz) olfactory nerve (ON) stimulation in the presence of NBQX and d-APV, blockers of ionotropic glutamate receptors, and that was associated with a local Ca2+ transient in the MC dendritic tuft. High-frequency ON stimulation in the presence of NBQX and d-APV also evoked a slow, nearly 2-Hz oscillation of MC membrane potential that was abolished by the mGluR1 antagonist LY367385 (50 μM). Both mGluR slow potential and slow oscillation persisted in the presence of gabazine (10 μM), a GABAA receptor antagonist, and intracellular QX-314 (10 mM), a Na+ channel blocker. In contrast to a slow mGluR1 potential in cerebellar Purkinje neurons, the MC mGluR1 potential was not depressed by SKF96365 (≤250 μM) and thus is likely not mediated by TRPC1 cation channels, nor was it potentiated by an elevation of intracellular Ca2+ level. Imaging with the Na+ indicator SBFI revealed a Na+ transient in the MC dendrite accompanying the mGluR1 slow potential. We conclude that the MC mGluR1 potential triggered by glutamate released from the ON supports oscillations and synchronizations of MCs associated within one glomerulus.

Activation of group II metabotropic glutamate receptors inhibits glutamate release from salamander retinal photoreceptors

2002 ◽  
Vol 19 (3) ◽  
pp. 275-281 ◽  
Author(s):  
MATTHEW H. HIGGS ◽  
PETER D. LUKASIEWICZ
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Ganglion Cells ◽  
Glutamate Release ◽  
Bipolar Cells ◽  
Horizontal Cells ◽  
Inward Current ◽  
Metabotropic Glutamate ◽  
Retinal Photoreceptors ◽  
Group Ii

We investigated the effects of group II metabotropic glutamate receptor (mGluR) activation on excitatory synaptic transmission in the salamander retinal slice preparation. The group II selective agonists DCG-IV and LY354740 reduced light-evoked excitatory postsynaptic currents (EPSCs) in ganglion cells. To determine the synaptic basis of this effect, we also recorded from bipolar cells and horizontal cells. In ON bipolar cells, DCG-IV increased the inward current in darkness but did not affect the peak current at light onset. In OFF bipolar cells and horizontal cells, DCG-IV had the opposite effect, reducing the inward current in darkness. Given the opposite polarities of these two classes of synapses, our results suggest that group II mGluRs act presynaptically to reduce glutamate release from photoreceptors. To determine whether DCG-IV affected rods or cones, we applied light stimuli that selectively activate each type of photoreceptor. In horizontal cells, most of which receive mixed synaptic input from rods and cones, DCG-IV reduced rod-driven EPSCs evoked by 470-nm stimuli and cone-driven EPSCs elicited by 700-nm stimuli in the presence of a rod-saturating background. Thus, activation of group II mGluRs reduced rod- and cone-mediated glutamate release. Our results suggest that group II mGluRs could mediate feedback by which extracellular glutamate inhibits glutamate release from photoreceptor terminals.

Pharmacological similarity between the retinal APB receptor and the family of metabotropic glutamate receptors

1994 ◽  
Vol 71 (6) ◽  
pp. 2258-2268 ◽  
Author(s):  
N. Tian ◽  
M. M. Slaughter
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Rank Order ◽  
Bipolar Cells ◽  
Receptor Protein ◽  
Cell Potential ◽  
Metabotropic Glutamate ◽  
The Family ◽  
Potent Agonist

1. We performed current-clamp and voltage-clamp experiments in the amphibian retina to examine the effects of 1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R ACPD), which is a selective agonist for the family of metabotropic glutamate receptors. 2. 1S,3R ACPD was found to selectively block the light responses of ON bipolar cells. It did not suppress the responses of horizontal cells of OFF bipolar cells. It blocked ON but not OFF responses of third-order retinal neurons. 3. 1S,3R ACPD mimicked the effect of the photoreceptor transmitter at the ON bipolar synapse. It reduced an inward current by a decrease in conductance. 4. The action of 1S,3R ACPD was very similar to that of 2-amino-4-phosphonobutyrate (APB) both in terms of effects on the ON bipolar cell potential and conductance and in terms of the retinal network. This suggests that the APB receptor is a predominant synaptic metabotropic glutamate receptor in the retina. 5. The rank-order potency at the retinal APB receptor is APB > 1S,3R ACPD > ibotenate. Quisqualate appears to be inactive at this receptor. The pharmacology of the retinal APB receptor matches that of the cloned mGluR4 and mGluR6 metabotropic glutamate receptors. On the basis of the in situ localization of mGluR6 to the inner nuclear layer of the retina, the retinal APB receptor may be this cloned receptor protein. 6. The effects of the three other ACPD stereo isomers were examined. 1S,3S ACPD was a weak agonist at the APB receptor. 1R,3R ACPD was a potent agonist in the inner retina, but inactive in the outer retina. This fits the profile of N-methyl-D-aspartate agonists. 1R,3S ACPD was inactive.

Retinal Bipolar Cell Input Mechanisms in Giant Danio. II. Patch-Clamp Analysis of on Bipolar Cells

2005 ◽  
Vol 93 (1) ◽  
pp. 94-107 ◽  
Author(s):  
Kwoon Y. Wong ◽  
Ethan D. Cohen ◽  
John E. Dowling
Keyword(s):  
Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Excitatory Amino Acid ◽  
Bipolar Cells ◽  
Evoked Responses ◽  
Excitatory Amino Acid Transporter ◽  
Light Responses ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Giant Danio

Glutamate receptors on giant danio retinal on bipolar cells were studied with whole cell patch clamping using a slice preparation. Cone-driven on bipolars (Cbs) and mixed-input on bipolars (Mbs) were identified morphologically. Most Cbs responded to the excitatory amino acid transporter (EAAT) substrate d-aspartate but not to the group III metabotropic glutamate receptor (mGluR) agonist l-(+)-2-amino-4-phosphonobutyric acid (l-AP4) or the AMPA/kainate receptor agonist kainate, suggesting EAATs are the primary glutamate receptors on Cbs. The EAAT inhibitor dl- threo-β-benzyloxyasparate (TBOA) blocked all light-evoked responses of Cbs, suggesting these responses are mediated exclusively by EAATs. Conversely, all Mbs responded to d-aspartate and l-AP4 but not to kainate, indicating they have both EAATs and group III mGluRs (presumably mGluR6). The light responses of Mbs involve both receptors because they could be blocked by TBOA plus (RS)-α-cyclopropyl-4-phosphonophenylglycine (CPPG, a group III mGluR antagonist) but not by either alone. Under dark-adapted conditions, the responses of Mbs to green (rod-selective) stimuli were reduced by CPPG but enhanced by TBOA. In contrast, both antagonists reduced the responses to red (cone-selective) stimuli, although TBOA was more effective. Furthermore, under photopic conditions, TBOA failed to eliminate light-evoked responses of Mbs. Thus on Mbs, rod inputs are mediated predominantly by mGluR6, whereas cone inputs are mediated mainly by EAATs but also by mGluR6 to some extent. Finally, we explored the interactions between EAATs and mGluR6 in Mbs. Responses to d-aspartate were reduced by l-AP4 and vice versa. Therefore mGluR6 and EAATs suppress each other, and this might underlie mutual suppression between rod and cone signals in Mbs.

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