Synaptic vesicle alterations in rod photoreceptors of synaptophysin-deficient mice

Spiwoks-Becker, Isabella; Vollrath, Lutz; Seeliger, M. W.; Jaissle, Gesine B.; Eshkind, Leonid; Leube, Rudolf E.

doi:10.1016/s0306-4522(01)00345-1

Cited by 85 publications

(77 citation statements)

References 72 publications

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“…3), which is abundantly expressed in the inner retinal neurons (14), the cellular source of OPs (1,3,22,23). Synaptophysin is indispensable for several presynaptic functions, including the release of neurotransmitters (24). The retinal levels of synaptophysin protein, reduced by inducing diabetes, were significantly (P Ͻ 0.01) reversed in 4-week diabetic mice by AT1R blockade with telmisartan or valsartan ( Fig.…”

Section: At1r-mediated Retinal Dysfunction In Diabetesmentioning

confidence: 89%

“…In the retina as well, pathogenic conditions such as retinal detachment and inflammation caused reduction of synaptophysin (14,39). Mice deficient in synaptophysin exhibited a significant decrease in the number of synaptic vesicles (24). The neuron maintains its viability and activity by interacting with other neurons via synapses; however, synaptophysin knockouts were for the most part functionally compensated possibly because of biological redundancy (24).…”

Section: At1r-mediated Retinal Dysfunction In Diabetesmentioning

confidence: 99%

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Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

et al. 2008

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OBJECTIVE-Pathogenic mechanisms underlying diabetesinduced retinal dysfunction are not fully understood. The aim of the present study was to show the relationship of the reninangiotensin system (RAS) with the synaptic vesicle protein synaptophysin and neuronal activity in the diabetic retina.RESEARCH DESIGN AND METHODS-C57BL/6 mice with streptozotocin-induced diabetes were treated with the angiotensin II type 1 receptor (AT1R) blocker telimsartan or valsartan, and retinal function was analyzed by electroretinography. Retinal production of the RAS components and phosphorylation of ERK (extracellular-signal regulated kinase) were examined by immunoblotting. Retinal mRNA and protein levels of synaptophysin were measured by quantitative RT-PCR and immunoblot analyses, respectively. In vitro, synaptophysin levels were also evaluated using angiotensin II-stimulated PC12D neuronal cells cultured with or without the inhibition of ERK signaling or the ubiquitin-proteasome system (UPS).RESULTS-Induction of diabetes led to a significant increase in retinal production of angiotensin II and AT1R together with ERK activation in the downstream of AT1R. AT1R blockade significantly reversed diabetes-induced electroretinography changes and reduction of synaptophysin protein, but not mRNA, levels in the diabetic retina. In agreement with the AT1R-mediated posttranscriptional downregulation of synaptophysin in vivo, in vitro application of angiotensin II to PC12D neuronal cells caused the UPS-mediated degradation of synaptophysin protein via AT1R, which proved to be induced by ERK activation.CONCLUSIONS-These data indicate the first molecular evidence of the RAS-induced synaptophysin degradation and neuronal dysfunction in the diabetic retina, suggesting the possibility of the AT1R blockade as a novel neuroprotective treatment for diabetic retinopathy.

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Section: At1r-mediated Retinal Dysfunction In Diabetesmentioning

confidence: 89%

Section: At1r-mediated Retinal Dysfunction In Diabetesmentioning

confidence: 99%

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

et al. 2008

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“…If this pool were evenly distributed across the 34 ribbon-style active zones (Figure 1), each active zone would possess ≈ 0.88 fF worth of releasable vesicles. Assuming a conversion factor of 25 aF/vesicle, obtained from the specific membrane capacitance of 9 fFμm -2 (Gentet et al, 2000) and a vesicle diameter of ≈ 30 nm (von Gersdorff et al, 1996;Spiwoks-Becker et al, 2001;Tsukamoto et al, 2001), the releasable pool of the mouse rod bipolar cell would correspond to nearly 1,200 vesicles or ≈ 35 vesicles per ribbon-style active zone. This is consistent with the predicted size of the releasable pool per ribbon synapse in the rat rod bipolar cell based upon data obtained from paired recordings (Singer & Diamond, 2006).…”

Section: Discussionmentioning

confidence: 99%

Synaptic vesicle dynamics in mouse rod bipolar cells

Wan¹,

Vila²,

Zhou³

et al. 2008

Vis Neurosci

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To better understand synaptic signaling at the mammalian rod bipolar cell terminal and pave the way for applying genetic approaches to the study of visual information processing in the mammalian retina, synaptic vesicle dynamics and intraterminal calcium were monitored in terminals of acutely isolated mouse rod bipolar cells and the number of ribbon-style active zones quantified. We identified a releasable pool, corresponding to a maximum of ≈ 35 vesicles/ribbon-style active zone. Following depletion, this pool was refilled with a time constant of ≈ 7 s. The presence of a smaller, rapidlyreleasing pool and a small, fast component of refilling were also suggested. Following calcium channel closure, membrane surface area was restored to baseline with a time constant that ranged from 2 to 21 seconds, depending upon the magnitude of the preceding Ca 2+ transient. In addition, a brief, calcium-dependent delay often preceded the start of onset of membrane recovery. Thus, several aspects of synaptic vesicle dynamics appear to be conserved between rod-dominant bipolar cells of fish and mammalian rod bipolar cells. A major difference is that the number of vesicles available for release is significantly smaller in the mouse rod bipolar cell, both as a function of the total number per neuron and on a per active zone basis.

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“…Two possibilities are transmitter-filled vesicles or vesicles involved in postsynaptic insertion of a membrane protein at horizontal cell endings. The presence of clear-cored vesicles Dowling & Boycott, 1966;Linberg & Fisher, 1988;Spiwoks-Becker et al, 2001! In several polarized cell types, syntaxin-4 localizes and targets proteins to the basolateral plasma membrane, whereas syntaxin-2~Hansen et al, 1999! or syntaxin-3~ter Beest et al, 2005!…”

Section: Pre-or Postsynaptic Function?mentioning

confidence: 99%

Robust syntaxin-4 immunoreactivity in mammalian horizontal cell processes

et al. 2007

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Horizontal cells mediate inhibitory feed-forward and feedback communication in the outer retina; however, mechanisms that underlie transmitter release from mammalian horizontal cells are poorly understood. Toward determining whether the molecular machinery for exocytosis is present in horizontal cells, we investigated the localization of syntaxin-4, a SNARE protein involved in targeting vesicles to the plasma membrane, in mouse, rat, and rabbit retinae using immunocytochemistry. We report robust expression of syntaxin-4 in the outer plexiform layer of all three species. Syntaxin-4 occurred in processes and tips of horizontal cells, with regularly spaced, thicker sandwich-like structures along the processes. Double labeling with syntaxin-4 and calbindin antibodies, a horizontal cell marker, demonstrated syntaxin-4 localization to horizontal cell processes; whereas, double labeling with PKC antibodies, a rod bipolar cell~RBC! marker, showed a lack of co-localization, with syntaxin-4 immunolabeling occurring just distal to RBC dendritic tips. Syntaxin-4 immunolabeling occurred within VGLUT-1-immunoreactive photoreceptor terminals and underneath synaptic ribbons, labeled by CtBP20RIBEYE antibodies, consistent with localization in invaginating horizontal cell tips at photoreceptor triad synapses. Vertical sections of retina immunostained for syntaxin-4 and peanut agglutinin~PNA! established that the prominent patches of syntaxin-4 immunoreactivity were adjacent to the base of cone pedicles. Horizontal sections through the OPL indicate a one-to-one co-localization of syntaxin-4 densities at likely all cone pedicles, with syntaxin-4 immunoreactivity interdigitating with PNA labeling. Pre-embedding immuno-electron microscopy confirmed the subcellular localization of syntaxin-4 labeling to lateral elements at both rod and cone triad synapses. Finally, co-localization with SNAP-25, a possible binding partner of syntaxin-4, indicated co-expression of these SNARE proteins in the same subcellular compartment of the horizontal cell. Taken together, the strong expression of these two SNARE proteins in the processes and endings of horizontal cells at rod and cone terminals suggests that horizontal cell axons and dendrites are likely sites of exocytotic activity.

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Synaptic vesicle alterations in rod photoreceptors of synaptophysin-deficient mice

Cited by 85 publications

References 72 publications

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

Angiotensin II Type 1 Receptor Signaling Contributes to Synaptophysin Degradation and Neuronal Dysfunction in the Diabetic Retina

Synaptic vesicle dynamics in mouse rod bipolar cells

Robust syntaxin-4 immunoreactivity in mammalian horizontal cell processes

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