Professor of Ophthalmology & Visual Science
Neuronal signals are processed in vertebrate CNS through parallel synaptic pathways. These synaptic pathways are formed with distinct cellular and molecular components and, in some cases, regulated by different mechanisms during development. In many parts of CNS, including visual system, a fundamental anatomical feature of the parallel synaptic pathways is the histologically discrete laminar structure. The cellular and molecular specificity of the laminar structure appears to be a major determinant of the specific synaptic pathways. In vertebrate retina, synaptic pathways processing different aspects of visual signals are also formed with different neuronal subtypes and synaptic structures in distinct laminae. This laminar structure is not mature at birth and continues to develop during postnatal ages in most mammalian retina. The goals of our research are to understand the cellular and molecular mechanisms, which regulate the development of the retinal synaptic pathways and the formation of the laminar structure, and how these mechanisms are modulated under normal and pathological conditions. Our principal strategies are to examine retinal ganglion cell (RGC) synaptic connectivity and activity at different stages of development under normal and pathological conditions and to test specific hypotheses using appropriate transgenic animal models.
Three-dimensional reconstruction of the dendritic structure of a RGC (green) and two dopaminergic amacrine cells (red).
To determine how RGC synaptic connectivity are regulated during normal development, we have examined the dendritic and axonal structure of RGCs using in vivo and in vitro confocal imaging and transgenic mouse models, in which green or yellow fluorescent proteins (GFP or YFP) are constitutively expressed in RGCs. We found that both RGC dendritic ramification in retina and axonal projection in the higher centers of the visual system, such as dLGN, undergo active refinement after birth in mice. This developmental refinement is regulated by retinal synaptic activity. Blockade of either spontaneous or light evoked retinal synaptic activity impaired the normal development of RGC synaptic connectivity in both retina and dLGN. Using laser confocal time-lapse imaging, we can visualize mouse RGC dendritic remodeling and quantify the kinetics of the morphological refinement. Using electrophysiological recordings, such as patch-clamp recording of synaptic activity of individual retinal neurons or multiple electrode array recording of concurrent spike activity from multiple RGCs, we detected significant maturational changes of RGC spontaneous synaptic activity and light responsiveness during postnatal development. These age-dependent changes of retinal synaptic activity play an important role in the maturation of synaptic circuitry of visual system. More recently, we are investigating the molecular mechanism which links the developmental changes of synaptic activity to the changes of synaptic structure. Surprisingly, we found that an immune molecule (CD3ζ, which is a key element of T-cell receptor), is expressed by retinal neurons and involves in the activity-dependent developmental regulation of RGC dendritic maturation in the retina and axonal projection in the dLGN.
Time-lapse image of a segment of RGC dendrites shows the dynamic changes of the dendritic protrusions of RGC in developing retina.
The results of these studies provide insights to how retinal synaptic circuitry could be changed during activity-dependent synaptic plasticity. They also have important implications in how we view pathologies that affect vision during infancy and childhood.
Fig 1 (dLGN).
Impaired eye-specific segregation of mouse RGC axonal projections in the dLGN due to pharmacological blockade of spontaneous synaptic activity mediated by glutamate receptor in retina.
Xu, H.P., Furman, M., Mineur, Y.S., Chen, H., King, S.L., Zenisek, D., Zhou, Z.J., Butts, D.A., Tian, N., Picciotto, M.R.,and Crair, M.C. (2011) Spontaneous retinal activity during development differentiates between visual maps for eye of origin and retinotoy. Neuron, in press.
Ding, C., Wang, P., and Tian, N. (2011) Effect of general anesthetics on IOP in elevated IOP mouse model. Exp Eye Res, 92:512-520.
He, Q., Wang, P., and Tian, N. (2011) Light-evoked synaptic activity of retinal ganglion and amacrine cells is regulated in developing mouse retina. Eur J Neurosci, 33:36-48.
Greten-Harrison, B., Polydoro, M., Morimoto-Tomita, M., Diao, L., Williams, A.M., Nie, E.H., Makani, S., Tian, N., Castillo, P.E., Buchman, V.L., and Chandra, S.S. (2010) αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction. Proc Natl Acad Sci USA, 107:19573-19578.
Xu, H.P., Chen, H., Ding, Q., Xie, Z.H., Chen, L., Diao, L., Wang, P., Gan, L., Crair, M.C., and Tian, N. (2010) Immune molecule, CD3ζ, is required for the development of neural circuit in retina. Neuron, 65:503-515.
Xu, H.P., and Tian, N. (2008) Glycine receptor-mediated synaptic transmission regulates the visual activity-dependent maturation of retinal ganglion cell synaptic connectivity. Journal of Comparative Neurology, 509:53-71.
Xu, H.P., and Tian, N. (2007) Retinal ganglion cell dendrites undergo a visual activity-dependent Redistribution after eye-opening. Journal of Comparative Neurology, 503:244-259.
Vistamehr, S., and Tian N. (2004) Light deprivation induced suppression of light response in mouse retina. Visual Neuroscience, 21:23-37.
Tian, N., and Copenhagen, D.R. (2003) Visual stimulation is required for refinement of ON and OFF pathways in postnatal retina. Neuron, 39:85-96.
Tian, N., and Copenhagen, D.R. (2001) Visual deprivation alters development of synaptic function in inner retina after eye opening. Neuron, 32:439-449.
Tian, N., Peterson, C., Kash, S., Baekkeskov, S., Copenhagen, D.R., and Nicoll, R.A. (1999) The roles of the synthetic enzyme GAD65 in the control of neuronal γ-aminobutyric acid release. Proc Natl Acad Sci U S A, 96:12911-12916.