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S. Bakalash, B. Tucker, C. Jiang, M. J. Young; Synapse Formation and Regeneration: The Possible Role of Neuroligins in Retinal Neurogenesis. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3572.
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© ARVO (1962-2015); The Authors (2016-present)
Recent years have seen a growing interest in retinal progenitor cell (RPC) transplantation as a possible therapeutic strategy for retinal degeneration. Despite expanding morphologic evidence for stem cell survival and differentiation, there is little knowledge of the connections between donor cells and host retinal neurons. While enhancement of RPC differentiation and integration remains an essential requirement for functional neural reconstitution, it is not sufficient if not accompanied by synaptic connections. Recent evidence highlights the importance of trans-synaptic interactions between newly-found postsynaptic Neuroligins and presynaptic Neurexins. These trans-membrane molecules bind extracellularly to promote adhesion between dendrites and axons, which in turn signals the further recruitment of presynaptic and postsynaptic molecules to form functional synapses. Here we explore the effects of Neurexins/Neuroligins (Nrx/Nlg) in RPC transplantation in retinal degeneration.
Nrx/Nlg effects were examined using in vivo and ex vivo mouse models of RPC transplantation into photoreceptor degenerated retinas vs. normal, age matched controls. Synapse formation and RPC integration were evaluated immunohistochemically following administration of different concentrations of Nrx/Nlg, or following transplantation of Nrx/Nlg -transfected RPCs, using various synaptic markers such as the pre synaptic Bassoon and post synaptic PSD-95. Quantification was done using SuperArray© gene analysis methods aimed at detecting synaptic as well as photoreceptor markers.
We found that exposure of the retinas to either Neuroligin 1 or Neurexin 1b promoted growth of RPCs processes to the outer plexiform layer (OPL) in the degenerated retinas, as well as co-localization with pre and post synaptic markers, when compared with controls. This was also shown quantitatively by densitometric gene array analysis. In contrast, Neuroligin 2 administration did not evoke synapse formation or RPC migration to the OPL. Nrx/Nlg-transfected RPCs displayed distinct arborization patterns and more migration and in-growth to the host synaptic layers.
Adding Neurexin 1b or Neuroligin 1 but not Neuroligin 2 along with RPCs to photoreceptor degeneration mouse models was found to promote synaptogenesis and increased RPC in-growth to the OPL. We suggest that neuroligin administration may therefore facilitate progenitor cell migration and assimilation while promoting restoration of function through formation of synaptic connections in the diseased retina.
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