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N. Tian, H.-P. Xu, H. Chen, L. Diao; T Lymphocyte Receptor-Mediated Immune Signals Regulate the Development of Retinal Synaptic Activity and Connectivity in the Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3844.
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T-cell receptor (TCR) mediated Class I major histocompatibility complex (MHCI) is known to be important for the activity-dependent maturation of RGC axonal projections in the LGN. The goal of this study is to determine whether TCR mediated signaling is important for the maturation of RGC synaptic connections in the retina.
Thy1-YFP and Thy1-YFP/CD3ζ-/- dual transgenic mice were used to study the development of RGC dendritic stratification and synaptic connections. A multielectrode array (MEA) system was used to record RGC spontaneous and light evoked action potentials. Electroretinogram (ERG) recordings were used to record the retinal light responses in vivo. Laser confocal microscopy was used to characterize the dendritic structure of RGCs and the kinetics of RGC dendritic growth and elimination in time-lapse imaging.
Our results showed that the frequency of the spontaneous retinal wave mediated by glutamatergic synaptic transmission (Stage III wave) was reduced in the CD3ζ-/- mice, while the spontaneous retinal wave mediated by cholinergic synaptic transmission (Stage II wave) was not affected. The reduction of the frequency of Stage III retinal wave was accompanied by a decrease of light evoked inner retinal responses measured as the ERG OPs with little effect on the light responses of outer retina measured as the ERG a- and b-waves. RGCs of CD3ζ-/- mice also showed a significantly reduced kinetics of dendritic growth and elimination before eye opening, which was associated with a 6-fold increase of the number of filopodia-like protrusions of RGC dendrites. In adult CD3ζ-/- mice, the dendrites of RGCs have increased density in nearly every morphological subtype and more diffusely ramified in the IPL. Functionally, CD3ζ-/- mice have a 40% increase in the number of RGCs receiving synaptic inputs from both ON and OFF bipolar cells and a 15% increase of the amplitude of the inner retinal light responses.
We concluded that TCR-mediated immune signals regulate the development of RGC synaptic connectivity in the retina through modulating glutamate receptor-mediated spontaneous retinal synaptic activity. Genetic deletion of CD3ζ subunit of TCR reduced the glutamatergic synaptic transmission before eye opening, which in turn reduced the turn over rate of RGC dendritic growth/elimination in young animals. Consequently, RGCs of adult CD3ζ-/- mice have more diffusely distributed dendrites, higher dendritic density, more synaptic connections with both ON and OFF bipolar cells and enhanced inner retinal light responses.
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