Neuronal plasticity is high during development and low at maturity. High plasticity enables developing circuits to refine their connections and attain specific functions, whereas low plasticity restricts rewiring in mature circuits, limiting functional recovery from neurodegeneration and injury. Our proposal focuses on three questions: (1) How do cell-type-specific plasticity mechanisms support the development of specific circuits? (2) What controls the maturational switch from high to low plasticity? (3) How can we enhance plasticity of mature neurons to promote functional recovery from neurodegeneration and injury? We will address these questions in retinal bipolar cells. Bipolar cells are second-order neurons of the visual system and relay photoreceptor signals from the outer retina to amacrine and ganglion cells in the inner retina. Bipolar cells lose input when photoreceptors die in retinal degeneration, the most common heritable cause of visual impairment (i.e., > 1:2000 people worldwide). Retinal degeneration, a heterogeneous group of diseases, often progresses slowly, leaving a window of opportunity, in which rewiring of bipolar cells with remaining photoreceptors could rescue vision.
In Aim 1 of our proposal, we will characterize the developmental plasticity of three bipolar cell types, which participate in two retinal circuits that support specific visually guided behaviors. Thus, we will link cell-type-specific plasticity mechanisms to the development of specific circuits and the behaviors they support.
In Aim 2, we will characterize molecules and mechanisms that contribute to the maturational switch from high to low plasticity in the same bipolar cells. We will translate insights into these molecules and mechanisms into viral tools to restore developmental plasticity to mature neurons.
In Aim 3, we will test the ability of these tools to rescue connectivity and function in two mouse models of retinal degeneration. Throughout this proposal, we will use adeno- associated viruses to manipulate plasticity. We will analyze bipolar cell morphology and connectivity by confocal and superresolution imaging. We will monitor circuit function by two-photon Ca2+ imaging and patch clamp electrophysiology, and we will test optokinetic responses and perceptual contrast sensitivity to assess visual function of mice. Together, these studies will provide insights into the expression and control mechanisms of plasticity and translate these insights into strategies to enhance plasticity of mature bipolar cells to rescue vision during retinal degeneration.

Public Health Relevance

This proposal aims to elucidate how developmental plasticity gives rise to specific circuits, to identify mechanisms that suppress plasticity in mature neurons, and to translate insights into these mechanisms into viral tools to restore developmental plasticity to mature neurons. The proposal focuses on bipolar cells and will test whether enhancing plasticity of mature bipolar cells can rescue visual function during retinal degeneration, the most common heritable cause of visual impairment.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023341-07
Application #
10085643
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Greenwell, Thomas
Project Start
2014-01-01
Project End
2022-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Johnson, Keith P; Zhao, Lei; Kerschensteiner, Daniel (2018) A Pixel-Encoder Retinal Ganglion Cell with Spatially Offset Excitatory and Inhibitory Receptive Fields. Cell Rep 22:1462-1472
Soto, Florentina; Zhao, Lei; Kerschensteiner, Daniel (2018) Synapse maintenance and restoration in the retina by NGL2. Elife 7:
Tien, Nai-Wen; Soto, Florentina; Kerschensteiner, Daniel (2017) Homeostatic Plasticity Shapes Cell-Type-Specific Wiring in the Retina. Neuron 94:656-665.e4
Hsiang, Jen-Chun; Johnson, Keith P; Madisen, Linda et al. (2017) Local processing in neurites of VGluT3-expressing amacrine cells differentially organizes visual information. Elife 6:
Kerschensteiner, Daniel; Guido, William (2017) Organization of the dorsal lateral geniculate nucleus in the mouse. Vis Neurosci 34:E008
Kim, Tahnbee; Kerschensteiner, Daniel (2017) Inhibitory Control of Feature Selectivity in an Object Motion Sensitive Circuit of the Retina. Cell Rep 19:1343-1350
Johnson, Robert E; Tien, Nai-Wen; Shen, Ning et al. (2017) Homeostatic plasticity shapes the visual system's first synapse. Nat Commun 8:1220
Tien, Nai-Wen; Kim, Tahnbee; Kerschensteiner, Daniel (2016) Target-Specific Glycinergic Transmission from VGluT3-Expressing Amacrine Cells Shapes Suppressive Contrast Responses in the Retina. Cell Rep 15:1369-1375
Kim, Tahnbee; Soto, Florentina; Kerschensteiner, Daniel (2015) An excitatory amacrine cell detects object motion and provides feature-selective input to ganglion cells in the mouse retina. Elife 4:
Akrouh, Alejandro; Kerschensteiner, Daniel (2015) Morphology and function of three VIP-expressing amacrine cell types in the mouse retina. J Neurophysiol 114:2431-8

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