The retina detects and transmits large amounts of visual information quickly and reliably. Ribbon synapses are key components of the vertebrate retinal circuitry, forming the first and second presynaptic elements in the signaling pathway to the brain. The specialized morphology and function of the ribbons presumably endows them with a unique capacity for copious and fast neurotransmitter release, which is thought to be essential for the efficient processing and encoding of visual information. Nevertheless, the underlying cellular mechanisms that modulate and maintain transmitter output from ribbon synapses under vastly different ambient light conditions and during the daytime/nighttime cycle are poorly understood. Due to their large size, we are able to patch-clamp single goldfish bipolar cell terminals. This allows us to measure both presynaptic Ca currents and evoked changes in membrane capacitance that assay synaptic vesicle exocytosis and endocytosis in real time. We have found that synaptic terminals have a greatly reduced efficiency of release at night, so that large Ca currents evoke small amounts of exocytosis. Conversely, relatively smaller Ca currents evoke much larger amounts of exocytosis during daytime. In addition, we have found that the well-known intermediate metabolites NAD+ and NADH modulate ribbon synapse output, perhaps via their interaction with a novel and major ribbon constituent protein RIBEYE. Thus, the first hypothesis to be tested is that the efficiency of exocytosis changes at a ribbon synapse in a circadian cycle (that parallels changes in ribbon morphology and metabolic state of the synapse), and that ribbon function is modulated by metabolites that reflect cellular energy levels. We have also found that elevated levels of internal Cl-ions inhibit the rate of endocytosis at ribbon synapses. Therefore, the second hypothesis to be tested is that Cl-influx via the strong GABAergic input at the terminal directly modulates the rate of vesicle recycling by inhibiting endocytosis, the first step in the recycling process. This finding suggests a novel role for Cl- ions as second messengers that modulate vesicle cycling. Finally, we have preliminary evidence that dephosphorylation drastically inhibits the mobility of synaptic vesicles within bipolar cell terminals. Very little is known about how ribbon synapses regulate vesicle mobility and clustering. The third hypothesis to be tested is that phosphorylation regulates vesicle recycling and mobility at ribbon synapses. These studies will thus increase our understanding of ribbon synapses as dynamic structures that adapt to diverse conditions so as to efficiently transmit a wide array of stimuli.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (ZRG1-VISC (01))
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Mariani, Andrew P
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Oregon Health and Science University
Schools of Medicine
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Kim, Mean-Hwan; von Gersdorff, Henrique (2016) Postsynaptic Plasticity Triggered by Ca²?-Permeable AMPA Receptor Activation in Retinal Amacrine Cells. Neuron 89:507-20
Taxidis, Jiannis; Anastassiou, Costas A; Diba, Kamran et al. (2015) Local Field Potentials Encode Place Cell Ensemble Activation during Hippocampal Sharp Wave Ripples. Neuron 87:590-604
Balakrishnan, Veeramuthu; Puthussery, Theresa; Kim, Mean-Hwan et al. (2015) Synaptic Vesicle Exocytosis at the Dendritic Lobules of an Inhibitory Interneuron in the Mammalian Retina. Neuron 87:563-75
Kim, Mean-Hwan; Li, Geng-Lin; von Gersdorff, Henrique (2013) Single Ca2+ channels and exocytosis at sensory synapses. J Physiol 591:3167-78
Vickers, Evan; Kim, Mean-Hwan; Vigh, Jozsef et al. (2012) Paired-pulse plasticity in the strength and latency of light-evoked lateral inhibition to retinal bipolar cell terminals. J Neurosci 32:11688-99
Cho, Soyoun; von Gersdorff, Henrique (2012) Ca(2+) influx and neurotransmitter release at ribbon synapses. Cell Calcium 52:208-16
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Vigh, Jozsef; Vickers, Evan; von Gersdorff, Henrique (2011) Light-evoked lateral GABAergic inhibition at single bipolar cell synaptic terminals is driven by distinct retinal microcircuits. J Neurosci 31:15884-93
Kim, Mean-Hwan; von Gersdorff, Henrique (2010) Extending the realm of membrane capacitance measurements to nerve terminals with complex morphologies. J Physiol 588:2011-2
Yamashita, Takayuki; Eguchi, Kohgaku; Saitoh, Naoto et al. (2010) Developmental shift to a mechanism of synaptic vesicle endocytosis requiring nanodomain Ca2+. Nat Neurosci 13:838-44

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