Calmodulin Bidirectionally Regulates Evoked and Spontaneous Neurotransmitter Release at Retinal Ribbon Synapses

Liang, Chao-Qun; Zhang, Gong; Zhang, Lei; Chen, Siyun; Wang, Junnan; Zhang, Tingting; Singer, Joshua H.; Ke, Jiang-Bin

doi:10.1523/eneuro.0257-20.2020

Cited by 11 publications

(15 citation statements)

References 83 publications

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“…The distinct roles that EAAT2 and EAAT5 may play in signal transmission at RB→AII synapses, however, remains elusive. It has been shown recently that, by expressing the light-sensitive cation channel ChR2 predominantly in RBs using cre-mediated recombination in the Pcp2-cre::Ai32 mouse retina, optogenetic stimulation of neurotransmission at RB→AII synapses could be stable over long periods (>20 min; Liang et al, 2021 ). To determine whether EAAT2 and EAAT5 contribute to synaptic transmission between RBs and AIIs, we blocked all the transmission from photoreceptors to second-order retinal neurons (i.e., BCs and horizontal cells) with the mGluR6 agonist L-AP4 (5 μ m ) and the kainate receptor antagonist ACET (1 μ m ) and used brief flashes (2–10 ms) of 470-nm LED light to activate RBs; optogenetically-evoked EPSCs and miniature EPSCs (mEPSCs) recorded in AIIs under this condition reflect evoked and spontaneous release from RBs, respectively ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To determine whether EAAT2 and EAAT5 contribute to synaptic transmission between RBs and AIIs, we blocked all the transmission from photoreceptors to second-order retinal neurons (i.e., BCs and horizontal cells) with the mGluR6 agonist L-AP4 (5 μ m ) and the kainate receptor antagonist ACET (1 μ m ) and used brief flashes (2–10 ms) of 470-nm LED light to activate RBs; optogenetically-evoked EPSCs and miniature EPSCs (mEPSCs) recorded in AIIs under this condition reflect evoked and spontaneous release from RBs, respectively ( Fig. 4 A ; Liang et al, 2021 ). As a control, no visible light-evoked EPSCs could be detected in AIIs from wild-type mice under the same experimental condition ( n = 2; data not shown).…”

Section: Resultsmentioning

confidence: 99%

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Glutamate Transporters EAAT2 and EAAT5 Differentially Shape Synaptic Transmission from Rod Bipolar Cell Terminals

Tang

Yuan

Liu

et al. 2022

eNeuro

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Excitatory amino acid transporters (EAATs) control visual signal transmission in the retina by rapidly removing glutamate released from photoreceptors and bipolar cells (BCs). Although it has been reported that EAAT2 and EAAT5 are expressed at presynaptic terminals of photoreceptors and some BCs in mammals, the distinct functions of these two glutamate transporters in retinal synaptic transmission, especially at a single synapse, remain elusive. In this study, we found that EAAT2 was expressed in all BC types while coexisting with EAAT5 in rod bipolar (RB) cells and several types of cone BCs from mice of either sex. Our immunohistochemical study, together with a recently published literature ( Gehlen et al., 2021 ), showed that EAAT2 and EAAT5 were both located in RB axon terminals near release sites. Optogenetic, electrophysiological and pharmacological analyses, however, demonstrated that EAAT2 and EAAT5 regulated neurotransmission at RB→AII amacrine cell synapses in significantly different ways: EAAT5 dramatically affected both the peak amplitude and kinetics of postsynaptic responses in AIIs, whereas EAAT2 had either relatively small or opposite effects. By contrast, blockade of EAAT1/GLAST, which was exclusively expressed in Müller cells, showed no obvious effect on AII responses, indicating that glutamate uptake by Müller cells did not influence synaptic transmission from RB terminals. Furthermore, we found that temporal resolution at RB→AII synapses was reduced substantially by blockade of EAAT5 but not EAAT2. Taken together, our work reveals the distinct functions of EAAT2 and EAAT5 in signal transmission at RB ribbon synapses.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Glutamate Transporters EAAT2 and EAAT5 Differentially Shape Synaptic Transmission from Rod Bipolar Cell Terminals

Tang

Yuan

Liu

et al. 2022

eNeuro

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“…Since VGCC blockers did not affect mEPSCs in CA3-PCs in the presence of calmidazolium, we concluded that the VGCC dependence of spontaneous release in CA3-PCs is mediated by calmodulin. Calmodulin regulates calcium channel activity and plays a role in synaptic vesicle release and recycling(Ben-Johny and Yue, 2014; Liang et al, 2021; Sakaba and Neher, 2001). The role of calmodulin in spontaneous release has not been reported in mammalian central synapses; however, calmodulin participates in spontaneous release at various synapses such as the Drosophila neuromuscular junction and rat retinal ribbon synapses through the v-ATPase subunit and myosin light chain kinase, respectively (Liang et al, 2021; Wang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Calmodulin regulates calcium channel activity and plays a role in synaptic vesicle release and recycling(Ben-Johny and Yue, 2014; Liang et al, 2021; Sakaba and Neher, 2001). The role of calmodulin in spontaneous release has not been reported in mammalian central synapses; however, calmodulin participates in spontaneous release at various synapses such as the Drosophila neuromuscular junction and rat retinal ribbon synapses through the v-ATPase subunit and myosin light chain kinase, respectively (Liang et al, 2021; Wang et al, 2014). The involvement of calmodulin implies that spontaneous release is not a passive phenomenon determined by the physical location of VGCCs and synaptic vesicles but can be modulated by physiological conditions that change the activity of calmodulin.…”

Section: Discussionmentioning

confidence: 99%

Voltage-gated calcium channels contribute to spontaneous glutamate release directly via nanodomain coupling or indirectly via calmodulin

Lee

Yang

Lee

et al. 2020

Preprint

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Neurotransmitter release occurs either synchronously to action potentials or spontaneously, yet whether molecular machineries underlying evoked and spontaneous release are identical, especially whether voltage-gated Ca2+ channels (VGCCs) can trigger spontaneous events has been in debate. To elucidate this issue, we characterized Ca2+ dependency of miniature excitatory postsynaptic currents (mEPSCs) in autaptic cultured hippocampal neurons. We found that 58 % mEPSC frequency was dependent on extracellular Ca2+([Ca2+]o), and Ca2+cooperativity of spontaneous release was comparable to that of evoked release. Moreover, most (> 90 %) of [Ca2+]o-dependent mEPSCs was attributable to VGCCs. Coupling distance between VGCCs and Ca2+ sensors was estimated as tight for both spontaneous and evoked release (~22 nm). In hippocampal slices, VGCC-dependence on spontaneous release was also observed, but to a different extent, at different areas and ages. At the calyx of Held synapses, mEPSCs showed VGCC-dependence in type 1 mature synapses where VGCCs and Ca2+ sensors are tightly coupled, but not in immature synapses. These data strongly suggest that the distance between VGCCs and Ca2+ sensors is the key factor to determine VGCC dependence of spontaneous release.

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“…Retinal slices were made according to the previous research. 27 Briefly, a part of the isolated retina was embedded in 2.5% agarose (Sigma-Aldrich, A0701, St. Louis, MO), which was dissolved in the buffer for agarose gel (NaCl 119 mM, HEPES 40 mM, NaH 2 PO 4 1.25 mM, KCl 2.5 mM, CaCl 2 · 2 O 1.15 mM and MgSO 4 1.5 mM) at 150°C and held at 37°C. This embedded retina was quickly cooled and stuck at the base of the slicer (Leica Biosystems, VT1200s, Wetzlar, Germany).…”

Section: Methodsmentioning

confidence: 99%

Identification of TPBG-Expressing Amacrine Cells in DAT-tdTomato Mouse

Huang

Liu

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Neurons are the bricks of the neuronal system and experimental access to certain neuron subtypes will be of great help to decipher neuronal circuits. Here, we identified trophoblast glycoprotein (TPBG)-expressing GABAergic amacrine cells (ACs) that were selectively labeled in DAT-tdTomato transgenic mice. Methods Retina and brain sections were prepared for immunostaining with antibodies against various biomarkers. Patch-sequencing was performed to obtain the transcriptomes of tdTomato-positive cells in DAT-tdTomato mice. Whole-cell recordings were conducted to identify responses to light stimulation. Results Tyrosine hydroxylase immunoreactive cells were colocalized with tdTomato-positive cells in substantia nigra pars compacta, but not in the retina. Transcriptomes collected from tdTomato-positive cells in retinas via Patch-sequencing exhibited the expression of marker genes of ACs ( Pax6 and Slc32a1 ) and marker genes of GABAergic neurons ( Gad1 , Gad2 , and Slc6a1 ). Immunostaining with antibodies against relevant proteins (GAD67, GAD65, and GABA) also confirmed transcriptomic results. Furthermore, tdTomato-positive cells in retinas selectively expressed Tpbg , a marker gene for distinct clusters molecularly defined, which was proved with TPBG immunoreactivity in fluorescently labeled cells. Finally, tdTomato-positive cells recorded showed ON–OFF responses to light stimulation. Conclusions Ectopic expression occurs in the retina but not in the substantia nigra pars compacta in the DAT-tdTomato mouse, and fluorescently labeled cells in the retina are TPBG-expressing GABAergic ACs. This type of transgenic mice has been proved as an ideal tool to achieve efficient labeling of a distinct subset of ACs that selectively express Tpbg .

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Calmodulin Bidirectionally Regulates Evoked and Spontaneous Neurotransmitter Release at Retinal Ribbon Synapses

Cited by 11 publications

References 83 publications

Glutamate Transporters EAAT2 and EAAT5 Differentially Shape Synaptic Transmission from Rod Bipolar Cell Terminals

Glutamate Transporters EAAT2 and EAAT5 Differentially Shape Synaptic Transmission from Rod Bipolar Cell Terminals

Voltage-gated calcium channels contribute to spontaneous glutamate release directly via nanodomain coupling or indirectly via calmodulin

Identification of TPBG-Expressing Amacrine Cells in DAT-tdTomato Mouse

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