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B. W. Jones, R. E. Marc, C. B. Watt, K. Kinard, D. DeMill, J.-H. Yang, T. Tasdizen, P. Koshevoy, E. Jurrus, R. Whitaker; Structure and Function of Microneuromas in Retinal Remodeling. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2487.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal remodeling triggered by retinal degenerations can lead to formation of new synaptic neuropil: microneuromas. The goals of our work are to visualize the fine structure, circuitry and functional attributes of microneuromas.
Models used include the human rhodopsin-GFP knock-in mouse (J Wilson, Baylor Col Med), an RGS9 truncation transgenic mouse (Jason C-K Chen, Virginia Commonwealth Univ) and the rd1 mouse. Postnatal day 100-450 mice were euthanized, eyes enucleated and fixed for visualization by computational molecular phenotyping (CMP; Jones et al., J Comp Neurol 2006;464: 1-16) or incubated for in vitro excitation mapping (Marc, J Comp Neurol 1999; 407:47-64) using 1-amino-4-guanidobutane (AGB) permeation activated by kainate or NMDA, followed by CMP. Some mice were used for in vivo AGB mapping of endogenous activity with 5 mM AGB in the eyecup for 45 min. Reconstructions of microneuromas were achieved by a combination of CMP and large-scale image tiling, registration and process tracking of serial high-resolution electron microscope imagery of microneuromas.
Reconstructions of microneuromas reveal bipolar, amacrine and ganglion cells. Though dominated by conventional GABAergic synapses, bipolar cells form abundant synaptic ribbon contacts with all classes of profiles in microneuromas. Microneuromas are partitioned into distinct structural zones: (1) Muller process ensheathment; (2) orderly fascicles of en passant processes that make few or no contacts; (3) tangles of processes forming numerous synaptic connections. Two reconstructed microneuromas demonstrate either direct contact with remnant retinal pigmented epithelial (RPE) cells or RPE root-like processes extending into the core of the microneuroma. Excitation mapping with kainate or NMDA activation in vitro demonstrates that microneuromas express abundant functional ionotropic glutamate receptors. In vivo excitation mapping shows that microneuromas have intrinsic excitation events, even in the absence of photoreceptor drive.
Microneuromas are complex structures with intrinsic neural derived processes from cells that express functional ionotropic glutamate receptors. Microneuroma formation is potentially triggered by contact with the RPE. As some processes in microneuromas derive from retinal ganglion cells, ectopic signaling complicates attempts to restore visual signaling with transplants or prosthetic devices.
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