May 2006
Volume 47, Issue 13
ARVO Annual Meeting Abstract  |   May 2006
Partial Circuitry Rescue By Cones In Retinitis Pigmentosa
Author Affiliations & Notes
  • B.W. Jones
    Ophthalmology, Moran Eye Center, Salt Lake City, UT
  • K. Kinnard
    Ophthalmology, Moran Eye Center, Salt Lake City, UT
  • D.W. Marshak
    Neurobiology and Anatomy, University Texas Medical School, Houston, UT
  • R.E. Marc
    Ophthalmology, Moran Eye Center, Salt Lake City, UT
  • Footnotes
    Commercial Relationships  B.W. Jones, None; K. Kinnard, None; D.W. Marshak, None; R.E. Marc, Signature Immunologics, E.
  • Footnotes
    Support  NIH Grants EY02576 (RM), EY06472 (DM), EY014800 Vision Core (RM)
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 2977. doi:
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      B.W. Jones, K. Kinnard, D.W. Marshak, R.E. Marc; Partial Circuitry Rescue By Cones In Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2977.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Retinal remodeling alters neuronal connectivity and survival in forms of retinitis pigmentosa (RP) where all photoreceptors are lost. But, what are the neural sequelae found in forms of cone–sparing RP? We used ex vivo excitation mapping and computational molecular phenotyping (CMP; Marc and Jones 2002 J Neurosci 22: 413) to probe signaling pathways in cone–sparing RP retinas.

Methods: : The hrhoG model (Chan et al., PNAS 101:9109) shows aggressive but inhomogeneous rod–cone degeneration, allowing concurrent assessment of ionotropic glutamate receptor (iGluR) drive in zones of complete rod–cone loss and islands of cone sparing. We used normal C57Bl6/J mice for comparison. We also acquired a rapid postmortem sample of human RP case (21 y.o. male). Consistent with the patient's history, the eye was rich in cones (albeit morphologically altered) and lacked rods. As a primate control, we used baboon (Papio anubis) retinas. Isolated eyecups or segments were incubated in a complete Ames medium augmented with 5 mM 1–amino–4–guanidobutane (AGB), an organic cation reporter that permeates glutamate–gated channels. Signaling pathways were activated with kainate (KA: 0, 0.003, .006, .012, or .025 mM) for 10 min. Characteristic small molecule signatures and AGB signals were visualized by CMP.

Results: : KA activates iGluRs on OFF bipolar cells (BCs). Combined with CMP, this parses BC signaling pathways into distinct cone ON, rod ON and AGB–labeled cone OFF populations in normal retinas. In hrhoG retinas with complete degeneration, BC signaling was absent, consistent with prior evidence that all BCs retract dendrites and down–regulate glutamate receptor expression. But, iGluR–mediated BC signaling was preserved beneath small patches of surviving cones. In the human RP case, KA activation roughly resembled normal primate and mammalian patterns, but rod BCs were absent and the number of OFF BCs appeared to have nearly doubled from a normal level of 39% to 79%. There was no evidence of BC death.

Conclusions: : Cone sparing in RP leads to nominal sparing of retinal circuitry, but the human RP case showed a remarkable increase in OFF BCs. We conclude that rod BCs, bereft of their normal contacts, switch dendrites to make novel contacts with cone pedicles and change gene expression, becoming functional OFF BCs by upregulating iGluR display. This anomalous rod BC survivor burden will lead to corrupted vision if the normal rod amacrine pathway remains intact in RP.

Keywords: retinal degenerations: cell biology • bipolar cells • retinal connections, networks, circuitry 

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