Visionrequiresthepreciseorganizationandfunctionofneuronalcircuitsintheretina.Our overallgoalhereistoadvancethebasicunderstandingofthecellularmechanismsthat regulatetheformationandthemaintenanceofsynapticconnectionsinthemammalian retina.Likeelsewhereinthenervoussystem,signalsnotonlyconvergeontoindividual neurons from multiple input types, but signals from an individual neuron are also distributed across multiple targets. Together, these two basic motifs of synaptic connectivity, convergence and divergence, underlie the complex but highly organized processing of neuronal information. Our knowledge of the mechanisms that sculpt stereotypicpatternsofconvergenceisexpanding.Incontrast,ourunderstandingofhow divergenceisshapedduringdevelopmentanddisruptedinneurodegenerativeconditions isscarce.Tofillthisgapinknowledge,wewillfocusontheAIIamacrinecellcircuitrythat is integral to the rod pathway, which is responsible for scotopic vision. This circuit will enableustogaininsightintothedevelopmentalmechanismsthatorganizeanexquisite arrangementofsynapticdivergenceatasinglesynapse(Aim1),aswellasmechanisms that distribute synapses from a single cell in a biased but consistent manner across distinct targets (Aim 2). We will use a combination of novel imaging approaches, electrophysiologyandtransgenicanimalsto:
(Aim1) Determinethecellularmechanisms thatorganizesynapticdivergenceattherodbipolarcell-AII/A17amacrinecelldyad,and ascertainthefactorsthatleadtodisruptionofthissynapseafterneurodegenerationdue toariseinintraocularpressure(IOP),and:
(Aim2) Determinethecellularprocessesthat shape output connections of AII amacrine cells onto bipolar cells and ganglion cells during normal development, and identify the processes that disrupt these connections upon IOP elevation. Together, our findings will greatly advance knowledge of the mechanismsresponsibleforprecisionincircuitassembly,aswellasoffernewknowledge ofhowthisprecisionbecomesalteredinconditionsofneuronaldegeneration.

Public Health Relevance

Theproperfunctioningofcircuitsinthenervoussystemrequirestheassemblyand maintenanceofprecisewiringpatternsofneurons.Thebroadgoalsofthisprojectareto improveourunderstandingofthecellularmechanismsthatareresponsibleforcircuit developmentinthevertebrateretinaandtoadvanceknowledgeofhowretinalcircuits becomedisruptedinconditionsofneuronaldegeneration.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-C (04)M)
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Greenwell, Thomas
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University of Washington
Anatomy/Cell Biology
Schools of Medicine
United States
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Kerov, Vasily; Laird, Joseph G; Joiner, Mei-Ling et al. (2018) ?2?-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses. J Neurosci 38:6145-6160
Zhang, Chi; Kolodkin, Alex L; Wong, Rachel O et al. (2017) Establishing Wiring Specificity in Visual System Circuits: From the Retina to the Brain. Annu Rev Neurosci 40:395-424
Ou, Yvonne; Jo, Rebecca E; Ullian, Erik M et al. (2016) Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses after Transient Ocular Hypertension. J Neurosci 36:9240-52
Della Santina, Luca; Kuo, Sidney P; Yoshimatsu, Takeshi et al. (2016) Glutamatergic Monopolar Interneurons Provide a Novel Pathway of Excitation in the Mouse Retina. Curr Biol 26:2070-2077
Chozinski, Tyler J; Halpern, Aaron R; Okawa, Haruhisa et al. (2016) Expansion microscopy with conventional antibodies and fluorescent proteins. Nat Methods 13:485-8
Dunn, Felice A (2015) Photoreceptor ablation initiates the immediate loss of glutamate receptors in postsynaptic bipolar cells in retina. J Neurosci 35:2423-31
Okawa, Haruhisa; Hoon, Mrinalini; Yoshimatsu, Takeshi et al. (2014) Illuminating the multifaceted roles of neurotransmission in shaping neuronal circuitry. Neuron 83:1303-1318
Hoon, Mrinalini; Okawa, Haruhisa; Della Santina, Luca et al. (2014) Functional architecture of the retina: development and disease. Prog Retin Eye Res 42:44-84
Dunn, Felice A; Wong, Rachel O L (2014) Wiring patterns in the mouse retina: collecting evidence across the connectome, physiology and light microscopy. J Physiol 592:4809-23
D'Orazi, Florence D; Suzuki, Sachihiro C; Wong, Rachel O (2014) Neuronal remodeling in retinal circuit assembly, disassembly, and reassembly. Trends Neurosci 37:594-603

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