The goals of this research are focused on understanding the signaling mechanisms that regulate the development of neural circuits and visual function in the maturing neonatal retina. Our own previous work, as well as that of others, has demonstrated that visual deprivation can suppress the normal maturation of dendritic arbors and the temporal properties of light responses of ganglion cells in the inner retina. We have found that the neurotrophin BDNF (Brain-Derived Neurotrophic Factor) is down regulated by visual deprivation and it plays a critical role, through activation of the TrkB receptor, in governing the refinement of more diffuse dendritic arbors of ON-OFF type ganglion cells into more narrowly stratified arbors that are restricted to ON and OFF synaptic regions of the inner plexiform layer of the retina. Other studies in brain have demonstrated that BDNF/TrkB signaling also regulates the formation of inhibitory synapses using GABA as a neurotransmitter. Because GABAergic neurotransmission plays such a critical role in visual processing in the retina we are proposing to test the hypothesis that BDNF/TrkB regulates the maturation of GABAergic circuits in the retina. Excitatory neurotransmission is also required for visual signaling in the retina. The excitatory inputs to retinal ganglion cells are mediated by glutamate release from bipolar cells that concomitantly activates two types of glutamate receptor, the NMDA- and AMPA-type. NMDA-type receptors are not only important for rapid signaling of neural signal but also play fundamental roles in the development of neuronal structures, the formation of functioning synapses and the modification of synaptic strength. NMDA receptor expression in the retina is itself regulated by light suggesting the activation of these receptors might, in turn, govern the maturation of synaptic connectivity and synapse function in the retina. We will be directly testing the hypothesis that NMDA receptors regulate the refinement of ganglion cell dendrites and the insertion of AMPA receptors into synaptic sites. We will employ genetic and pharmacological method to block both BDNF/TrkB signaling and NMDA receptor expression and function. In a final aim we will test the hypothesis that melanopsin expressing ganglion cells mediate a visual behavior, called negative phototaxis, in very young neonatal mice. We have preliminary evidence that the melanopsin containing ganglion cells, which are independent of rods and cones and are light responsive well before rod and cone visual signaling begins, are the photodetectors for this early visual behavior. Although melanopsin ganglion cells are known to control pupil responses and photoentrainment of circadian rhythms, this proposed early neonatal function for melanopsin has not been described previously. These experiments are designed to provide insight to how the visual system develops, what processes might lead to dysfunctional vision and what compensatory visual mechanisms might be functioning in blindness when rod and cone function is compromised.

Public Health Relevance

This proposal seeks to understand the mechanisms that govern the development of vision in the retina and to investigate the possibility of vision before the onset of rod and cone function. Understanding the processes that regulate the maturation of visual function and neural circuits in the retina will guide diagnosis and therapeutic approaches to restore or rescue blinding diseases in youth and in older adults.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY001869-35
Application #
8298177
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
1977-02-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
35
Fiscal Year
2012
Total Cost
$367,092
Indirect Cost
$129,492
Name
University of California San Francisco
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Yoshida, Miho; Feng, Liang; Grimbert, Francois et al. (2011) Overexpression of neurotrophin-3 stimulates a second wave of dopaminergic amacrine cell genesis after birth in the mouse retina. J Neurosci 31:12663-73
Johnson, Juliette; Wu, Vincent; Donovan, Michael et al. (2010) Melanopsin-dependent light avoidance in neonatal mice. Proc Natl Acad Sci U S A 107:17374-8
Liu, Xiaorong; Robinson, Michael L; Schreiber, Ann Marie et al. (2009) Regulation of neonatal development of retinal ganglion cell dendrites by neurotrophin-3 overexpression. J Comp Neurol 514:449-58
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Grishanin, Ruslan N; Yang, Haidong; Liu, Xiaorong et al. (2008) Retinal TrkB receptors regulate neural development in the inner, but not outer, retina. Mol Cell Neurosci 38:431-43
Johnson, Juliette; Fremeau Jr, Robert T; Duncan, Jacque L et al. (2007) Vesicular glutamate transporter 1 is required for photoreceptor synaptic signaling but not for intrinsic visual functions. J Neurosci 27:7245-55
Liu, Xiaorong; Grishanin, Ruslan N; Tolwani, Ravi J et al. (2007) Brain-derived neurotrophic factor and TrkB modulate visual experience-dependent refinement of neuronal pathways in retina. J Neurosci 27:7256-67
Bjartmar, Lisa; Huberman, Andrew D; Ullian, Erik M et al. (2006) Neuronal pentraxins mediate synaptic refinement in the developing visual system. J Neurosci 26:6269-81
Duncan, Jacque L; Yang, Haidong; Doan, Thuy et al. (2006) Scotopic visual signaling in the mouse retina is modulated by high-affinity plasma membrane calcium extrusion. J Neurosci 26:7201-11

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