Developing neural circuits undergo critical periods of refinement to establish precise connectivity. During these critical periods, neuronal activity and programmed cell death (PCD) shape the anatomy and function of neurons (i.e. neuronal plasticity). Dysregulation of plasticity has been identified as a common step in the etiology of neurodevelopmental disorders such as autism and schizophrenia. Neuronal plasticity encompasses axon and dendrite remodeling, synapse formation and elimination, changes in the molecular architecture of pre- and postsynaptic specializations, and adjustments to intrinsic excitability. While much is known about the regulation and action of individual plasticity mechanisms, how different plasticity mechanisms cooperate during neural development is not well understood. Recent evidence indicates that crosstalk between these mechanisms governs their function , and suggests that the interplay of plasticity mechanism depends on neuron type and in vivo circuit context. Here, we propose to study how diverse plasticity mechanisms cooperate across different levels of in vivo neural organization (synapse, neuron and circuit), in different cellular compartments (dendrite and axon), and in response to different triggers (neuronal activity and PCD) to shape the development and function of retinal bipolar cells (BCs), glutamatergic second order neurons of the visual system. Towards this end, we have generated transgenic mouse lines that selectively interfere with synaptic input to or output from BCs, or in which BCs can be removed in a graded manner concurrent with their naturally occurring PCD. To analyze structural and functional plasticity, we have established optical approaches from superresolution microscopy, to confocal reconstructions and 2-photon live imaging and optimized methods for targeted patch-clamp and anatomically aligned multielectrode array (MEA) recordings. Thus, we aim to provide an integrated view how diverse activity- and cell- density-dependent plasticity mechanisms cooperate to guide the development of a specific class of neurons and their integration into precise circuits in vivo.

Public Health Relevance

This proposal aims to provide insight into the mechanisms by which developing neurons adapt to changing cellular interactions (i.e. neuronal plasticity). A better understanding of neuronal plasticity has important clinical ramifications: (i) for the understanding and treatment of retinal diseases that trigger maladaptive forms of plasticity (e.g. Retinitis pigmentosa, age-related macular degeneration), (ii) for the rational design of neuron replacement therapies (e.g. photoreceptor transplantation), and (iii) for insight into neurodevelopmental disorders caused by dysregulations of plasticity.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Greenwell, Thomas
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Washington University
Schools of Medicine
Saint Louis
United States
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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
Tien, Nai-Wen; Pearson, James T; Heller, Charles R et al. (2015) Genetically Identified Suppressed-by-Contrast Retinal Ganglion Cells Reliably Signal Self-Generated Visual Stimuli. J Neurosci 35:10815-20
Soto, Florentina; Kerschensteiner, Daniel (2015) Synaptic remodeling of neuronal circuits in early retinal degeneration. Front Cell Neurosci 9:395

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