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Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses after Transient Ocular Hypertension.
J Neurosci. 2016 08 31; 36(35):9240-52.JN

Abstract

Key issues concerning ganglion cell type-specific loss and synaptic changes in animal models of experimental glaucoma remain highly debated. Importantly, changes in the structure and function of various RGC types that occur early, within 14 d after acute, transient intraocular pressure elevation, have not been previously assessed. Using biolistic transfection of individual RGCs and multielectrode array recordings to measure light responses in mice, we examined the effects of laser-induced ocular hypertension on the structure and function of a subset of RGCs. Among the α-like RGCs studied, αOFF-transient RGCs exhibited higher rates of cell death, with corresponding reductions in dendritic area, dendritic complexity, and synapse density. Functionally, OFF-transient RGCs displayed decreases in spontaneous activity and receptive field size. In contrast, neither αOFF-sustained nor αON-sustained RGCs displayed decreases in light responses, although they did exhibit a decrease in excitatory postsynaptic sites, suggesting that synapse loss may be one of the earliest signs of degeneration. Interestingly, presynaptic ribbon density decreased to a greater degree in the OFF sublamina of the inner plexiform layer, corroborating the hypothesis that RGCs with dendrites stratifying in the OFF sublamina may be damaged early. Indeed, OFF arbors of ON-OFF RGCs lose complexity more rapidly than ON arbors. Our results reveal type-specific differences in RGC responses to injury with a selective vulnerability of αOFF-transient RGCs, and furthermore, an increased susceptibility of synapses in the OFF sublamina. The selective vulnerability of specific RGC types offers new avenues for the design of more sensitive functional tests and targeted neuroprotection.

SIGNIFICANCE STATEMENT

Conflicting reports regarding the selective vulnerability of specific retinal ganglion cell (RGC) types in glaucoma exist. We examine, for the first time, the effects of transient intraocular pressure elevation on the structure and function of various RGC types. Among the α-like RGCs studied, αOFF-transient RGCs are the most vulnerable to transient transient intraocular pressure elevation as measured by rates of cell death, morphologic alterations in dendrites and synapses, and physiological dysfunction. Specifically, we found that presynaptic ribbon density decreased to a greater degree in the OFF sublamina of the inner plexiform layer. Our results suggest selective vulnerability both of specific types of RGCs and of specific inner plexiform layer sublaminae, opening new avenues for identifying novel diagnostic and treatment targets in glaucoma.

Authors+Show Affiliations

Department of Ophthalmology, University of California, San Francisco, San Francisco, California 94143, yvonne.ou@ucsf.edu luca.dellasantina@gmail.com.Department of Ophthalmology, University of California, San Francisco, San Francisco, California 94143.Department of Ophthalmology, University of California, San Francisco, San Francisco, California 94143.Department of Biological Structure, University of Washington, Seattle, Washington 98195, and.Department of Biological Structure, University of Washington, Seattle, Washington 98195, and Department of Pharmacy, University of Pisa, Pisa, Italy 56126 yvonne.ou@ucsf.edu luca.dellasantina@gmail.com.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27581463

Citation

Ou, Yvonne, et al. "Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses After Transient Ocular Hypertension." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 36, no. 35, 2016, pp. 9240-52.
Ou Y, Jo RE, Ullian EM, et al. Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses after Transient Ocular Hypertension. J Neurosci. 2016;36(35):9240-52.
Ou, Y., Jo, R. E., Ullian, E. M., Wong, R. O., & Della Santina, L. (2016). Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses after Transient Ocular Hypertension. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 36(35), 9240-52. https://doi.org/10.1523/JNEUROSCI.0940-16.2016
Ou Y, et al. Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses After Transient Ocular Hypertension. J Neurosci. 2016 08 31;36(35):9240-52. PubMed PMID: 27581463.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective Vulnerability of Specific Retinal Ganglion Cell Types and Synapses after Transient Ocular Hypertension. AU - Ou,Yvonne, AU - Jo,Rebecca E, AU - Ullian,Erik M, AU - Wong,Rachel O L, AU - Della Santina,Luca, PY - 2016/03/21/received PY - 2016/07/20/accepted PY - 2017/03/03/pmc-release PY - 2016/9/2/entrez PY - 2016/9/2/pubmed PY - 2017/8/18/medline KW - RGC type KW - dendrite KW - glaucoma KW - light response KW - retinal ganglion cell KW - synapse SP - 9240 EP - 52 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 36 IS - 35 N2 - UNLABELLED: Key issues concerning ganglion cell type-specific loss and synaptic changes in animal models of experimental glaucoma remain highly debated. Importantly, changes in the structure and function of various RGC types that occur early, within 14 d after acute, transient intraocular pressure elevation, have not been previously assessed. Using biolistic transfection of individual RGCs and multielectrode array recordings to measure light responses in mice, we examined the effects of laser-induced ocular hypertension on the structure and function of a subset of RGCs. Among the α-like RGCs studied, αOFF-transient RGCs exhibited higher rates of cell death, with corresponding reductions in dendritic area, dendritic complexity, and synapse density. Functionally, OFF-transient RGCs displayed decreases in spontaneous activity and receptive field size. In contrast, neither αOFF-sustained nor αON-sustained RGCs displayed decreases in light responses, although they did exhibit a decrease in excitatory postsynaptic sites, suggesting that synapse loss may be one of the earliest signs of degeneration. Interestingly, presynaptic ribbon density decreased to a greater degree in the OFF sublamina of the inner plexiform layer, corroborating the hypothesis that RGCs with dendrites stratifying in the OFF sublamina may be damaged early. Indeed, OFF arbors of ON-OFF RGCs lose complexity more rapidly than ON arbors. Our results reveal type-specific differences in RGC responses to injury with a selective vulnerability of αOFF-transient RGCs, and furthermore, an increased susceptibility of synapses in the OFF sublamina. The selective vulnerability of specific RGC types offers new avenues for the design of more sensitive functional tests and targeted neuroprotection. SIGNIFICANCE STATEMENT: Conflicting reports regarding the selective vulnerability of specific retinal ganglion cell (RGC) types in glaucoma exist. We examine, for the first time, the effects of transient intraocular pressure elevation on the structure and function of various RGC types. Among the α-like RGCs studied, αOFF-transient RGCs are the most vulnerable to transient transient intraocular pressure elevation as measured by rates of cell death, morphologic alterations in dendrites and synapses, and physiological dysfunction. Specifically, we found that presynaptic ribbon density decreased to a greater degree in the OFF sublamina of the inner plexiform layer. Our results suggest selective vulnerability both of specific types of RGCs and of specific inner plexiform layer sublaminae, opening new avenues for identifying novel diagnostic and treatment targets in glaucoma. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/27581463/Selective_Vulnerability_of_Specific_Retinal_Ganglion_Cell_Types_and_Synapses_after_Transient_Ocular_Hypertension_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=27581463 DB - PRIME DP - Unbound Medicine ER -