This study addresses the relationship between the specialized structure of the mammalian cone photoreceptor synapse and signaling in postsynaptic bipolar cell pathways that are critical for visual perception. Cone photoreceptors mediate vision under conditions of bright illumination and use glutamate as their transmitter. A cone contacts two functional classes of bipolar cells, On and Off, which have different glutamate receptors that cause them to depolarize (i.e., signal) either at light-on or light-off, respectively. Each functional class of bipolar cell is further subdivided into 4-5 anatomical subtypes (e.g., b2, b3, b7). Recent work has shown that the different anatomical subtypes of Off bipolar cells express different types of glutamate receptors (AMPA or kainate), make different numbers of contacts with a cone terminal, and contact the cone terminal at distinct distances from transmitter release sites. The differences in transmitter diffusion distance, contact number, and receptor type suggest that each subtype of Off bipolar cell could process a different component of the cone signal. The main goal of this project is to determine the properties of the signals in the different subtypes of Off bipolar cells, and to relate those properties to the structure and pharmacology of the synapse. Transmission at the cone to Off bipolar cell synapse will be studied by simultaneously voltage clamping a presynaptic cone and a postsynaptic bipolar cell in slices from the cone dominant retina of the ground squirrel.
The aim of the first set of experiments is to test the hypothesis that the b2 cell synapse is specialized to transmit high frequency fluctuations in cone voltage, and examine the underlying mechanisms. Specific experiments will a) determine how the amplitude of the transient depolarization at light-off varies with light pulse duration and b) use temporal flicker to determine the frequencies best transmitted by cone to Off bipolar cell synapses.
The aim of the second set of experiments is to test the hypothesis that the gain of steady synaptic transmission is different at cone to b3 and b7 cell synapses. Specific experiments will determine how cone contact number and receptor desensitization affect steady synaptic gain.
The aim of the third set of experiments is to test the hypothesis that cone glutamate transporters play only a small role in controlling the cleft glutamate concentration. Specific experiments will determine the extent to which ground squirrel cones recapture released glutamate and determine the locations of glutamate transporters relative to ribbon release sites.

Public Health Relevance

The goal of this project is to understand how the elaborate structure of the mammalian cone synapse determines its function in vision. Ultimately, diseases involving cone photoreceptor degeneration will be treated by either implanting exogenous cones or growing new cones from endogenous stem cells. The degree to which such approaches succeed may be governed by the ability of the cones to make structurally correct synaptic contacts with other cells in the retina.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Greenwell, Thomas
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Northwestern University at Chicago
Schools of Medicine
United States
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Grabner, Chad P; Ratliff, Charles P; Light, Adam C et al. (2016) Mechanism of High-Frequency Signaling at a Depressing Ribbon Synapse. Neuron 91:133-45
Lindstrom, Sarah H; Ryan, David G; Shi, Jun et al. (2014) Kainate receptor subunit diversity underlying response diversity in retinal off bipolar cells. J Physiol 592:1457-77
Light, Adam C; Zhu, Yongling; Shi, Jun et al. (2012) Organizational motifs for ground squirrel cone bipolar cells. J Comp Neurol 520:2864-87
Szmajda, Brett A; Devries, Steven H (2011) Glutamate spillover between mammalian cone photoreceptors. J Neurosci 31:13431-41
Li, Wei; Chen, Shan; DeVries, Steven H (2010) A fast rod photoreceptor signaling pathway in the mammalian retina. Nat Neurosci 13:414-6
Li, Wei; DeVries, Steven H (2006) Bipolar cell pathways for color and luminance vision in a dichromatic mammalian retina. Nat Neurosci 9:669-75
DeVries, Steven H; Li, Wei; Saszik, Shannon (2006) Parallel processing in two transmitter microenvironments at the cone photoreceptor synapse. Neuron 50:735-48
Li, Wei; DeVries, Steven H (2004) Separate blue and green cone networks in the mammalian retina. Nat Neurosci 7:751-6
DeVries, Steven H; Qi, Xiaofeng; Smith, Robert et al. (2002) Electrical coupling between mammalian cones. Curr Biol 12:1900-7
DeVries, S H (2001) Exocytosed protons feedback to suppress the Ca2+ current in mammalian cone photoreceptors. Neuron 32:1107-17

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