Activity-dependent synaptic remodeling is a fundamental feature for both normal development and degenerative diseases of CNS. A critical barrier to fully understand activity-dependent remodeling of neuronal circuitry of CNS is the lack of the knowledge of how neuronal structure is regulated by synaptic activity. Recent studies have demonstrated that proteins typically associated with the immune system are expressed by neurons and regulate activity-dependent synaptic plasticity in the normal development of CNS and pathogenesis of many CNS diseases. Therefore, studies to identify the function of immune molecules in the synaptic remodeling of retina will provide the foundation for the understanding of the molecular and synaptic mechanisms essential for the pathogenesis in degenerative retinal diseases. The long-term goal of this study is to identify the mechanism that regulates RGC dendritic remodeling under the control of synaptic activity and T-cell receptor (TCR). We recently found that a key component of TCR, CD3?, is expressed in RGCs. Genetic deletion of CD3? significantly impairs the normal development of RGC axons and dendrites. Pharmacological blockage of glutamate receptor (GluR)-mediated synaptic activity in WT mice phenocopies the defects observed in CD3?-/- mice but has no additional effect in CD3? mutants, suggesting that CD3? could play a critical role in GluR-mediated dendritic remodeling of RGCs. Because a primary function of CD3? in immune cells is to regulate cell morphology by reorganizing cytoskeleton, we propose to further investigate whether CD3? directly regulates RGC dendrites via cytoskeleton reorganization. Additionally, we will determine whether GluR-mediated synaptic activity is required for the CD3?-mediated regulation of RGC dendritic remodeling.
The first aim of this study is to determine whether CD3? directly and selectively regulates the dendritic remodeling of RGCs by examining RGC dendrites with gain-of-function of CD3? in RGCs through AAV2 virus induced expression of CD3? in CD3?-/- retinas.
The second aim will investigate how CD3? interacts with RGC synaptic activity during development by determining whether CD3? regulates RGC dendritic remodeling without or with GluR-mediated synaptic activity.
The third aim i s to determine whether CD3? regulates RGC dendritic remodeling through Fyn/ZAP70-mediated signaling pathway by examining whether mutation/knockdown of Fyn and ZAP70 impairs RGC dendritic remodeling as that of CD3? deletion, and whether Fyn and ZAP70 interact with CD3?-mediated activity in the regulation of RGC dendritic remodeling. The results of these studies would not only provide important insights into how immune molecules regulate development of retinal synaptic circuits but also address the fundamental question of how changes of synaptic activity lead to changes of neuronal morphology in activity-dependent synaptic plasticity.

Public Health Relevance

Understanding of how neuronal networks of the central nervous system (CNS) are formed during normal development and remodeled under pathological conditions will provide biological basis for the development of treatment strategies to preserve and reestablish the structure and function of the CNS in neuronal diseases. This proposed study will address the question of how synaptic activity and immune molecules regulate the development of retinal ganglion cell (RGC) dendrites. Accomplishment of the experiments proposed in this study would not only open up new areas of research for mechanisms of activity-dependent synaptic plasticity in the CNS but also stimulate future studies of the roles of immune molecules in pathogenesis and treatment of various neuronal diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Utah
Schools of Medicine
Salt Lake City
United States
Zip Code
Xu, Hong-Ping; Sun, Jin Hao; Tian, Ning (2014) A general principle governs vision-dependent dendritic patterning of retinal ganglion cells. J Comp Neurol 522:3403-22
Chen, Hui; Liu, Xiaorong; Tian, Ning (2014) Subtype-dependent postnatal development of direction- and orientation-selective retinal ganglion cells in mice. J Neurophysiol 112:2092-101
Kang, Nak Heon; Kim, Soon Je; Song, Seung Han et al. (2013) Hydroxyapatite synthesis using EDTA. J Craniofac Surg 24:1042-5
Schmidt, Joshua; Ehasz, Clayton; Epperson, Michael et al. (2013) The effect of the hydrophobic environment on the retro-aldol reaction: comparison to a computationally-designed enzyme. Org Biomol Chem 11:8419-25
Amini, Navid; Vahdatpour, Alireza; Xu, Wenyao et al. (2012) Cluster Size Optimization in Sensor Networks with Decentralized Cluster-Based Protocols. Comput Commun 35:207-220
Barabas, Peter; Huang, Wei; Chen, Hui et al. (2011) Missing optomotor head-turning reflex in the DBA/2J mouse. Invest Ophthalmol Vis Sci 52:6766-73
Xu, Hong-ping; Furman, Moran; Mineur, Yann S et al. (2011) An instructive role for patterned spontaneous retinal activity in mouse visual map development. Neuron 70:1115-27
Ding, Chun; Wang, Ping; Tian, Ning (2011) Effect of general anesthetics on IOP in elevated IOP mouse model. Exp Eye Res 92:512-20
He, Quanhua; Wang, Ping; Tian, Ning (2011) Light-evoked synaptic activity of retinal ganglion and amacrine cells is regulated in developing mouse retina. Eur J Neurosci 33:36-48
Terzis, Ioannis; Haritanti, Afrodite; Economou, Ipoliti (2010) Fibrolamellar hepatocellular carcinoma: a case report with distinct radiological features. J Gastrointest Cancer 41:2-5

Showing the most recent 10 out of 18 publications