Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1)

Yonju Ha, Alan Saul, Amany Tawfik, Cory Williams, Kathryn Bollinger, Robert Smith, Masanori Tachikawa, Eric Zorrilla, Vadivel Ganapathy, Sylvia B. Smith

Research output: Contribution to journalArticle

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Abstract

Purpose. Sigma receptor 1 (σR1) is expressed abundantly in the eye, and several reports suggest that this putative molecular chaperone plays a role in lens cell survival, control of intraocular pressure (IOP), and retinal neuroprotection. The present study examined the consequence of the absence of σR1 on ocular development, structure, and function. Methods. Wild-type (σR1 +/+), heterozygous (σR1 +/-), and homozygous (σR1 -/-, knockout) mice aged 5 to 59 weeks were subjected to comprehensive electrophysiological testing and IOP measurement. The eyes were examined by light and electron microscopy and subjected to morphometric examination and detection of apoptosis. Results. Cornea and lens of σR1 -/- mice were similar to wild-type mice in morphologic appearance at all ages examined, and IOP was within normal limits. Comprehensive ERG and morphometric analyses initially yielded normal findings in the σR1 -/- mice compared with those in the wild-type. By 12 months, however, significantly decreased ERG b-wave amplitudes and diminished negative scotopic threshold responses, consistent with inner retinal dysfunction, were detected in σR1 -/- mice. Concomitant with these late-onset changes were increased TUNEL- and active caspase 3-positive cells in the inner retina and significant loss of cells in the ganglion cell layer, particularly in the central retina. Before these functional and structural abnormalities, there was ultrastructural evidence of axonal disruption in the optic nerve head of σR1 -/- mice as early as 6 months of age, although there were no alterations observed in retinal vascularization in σR1 -/- mice. Conclusions. These data suggest that lack of σR1 leads to development of late-onset retinal dysfunction with similarities to optic neuropathy.

Original languageEnglish (US)
Pages (from-to)7749-7760
Number of pages12
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number10
DOIs
StatePublished - Sep 2011
Externally publishedYes

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Intraocular Pressure
Lenses
Retina
Optic Nerve Diseases
Molecular Chaperones
Optic Disk
In Situ Nick-End Labeling
Knockout Mice
Ganglia
Caspase 3
Cornea
sigma-1 receptor
Cell Survival
Electron Microscopy
Apoptosis
Light

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Ha, Y., Saul, A., Tawfik, A., Williams, C., Bollinger, K., Smith, R., ... Smith, S. B. (2011). Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1). Investigative Ophthalmology and Visual Science, 52(10), 7749-7760. https://doi.org/10.1167/iovs.11-8169

Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1). / Ha, Yonju; Saul, Alan; Tawfik, Amany; Williams, Cory; Bollinger, Kathryn; Smith, Robert; Tachikawa, Masanori; Zorrilla, Eric; Ganapathy, Vadivel; Smith, Sylvia B.

In: Investigative Ophthalmology and Visual Science, Vol. 52, No. 10, 09.2011, p. 7749-7760.

Research output: Contribution to journalArticle

Ha, Y, Saul, A, Tawfik, A, Williams, C, Bollinger, K, Smith, R, Tachikawa, M, Zorrilla, E, Ganapathy, V & Smith, SB 2011, 'Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1)', Investigative Ophthalmology and Visual Science, vol. 52, no. 10, pp. 7749-7760. https://doi.org/10.1167/iovs.11-8169
Ha, Yonju ; Saul, Alan ; Tawfik, Amany ; Williams, Cory ; Bollinger, Kathryn ; Smith, Robert ; Tachikawa, Masanori ; Zorrilla, Eric ; Ganapathy, Vadivel ; Smith, Sylvia B. / Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1). In: Investigative Ophthalmology and Visual Science. 2011 ; Vol. 52, No. 10. pp. 7749-7760.
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AU - Saul, Alan

AU - Tawfik, Amany

AU - Williams, Cory

AU - Bollinger, Kathryn

AU - Smith, Robert

AU - Tachikawa, Masanori

AU - Zorrilla, Eric

AU - Ganapathy, Vadivel

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AB - Purpose. Sigma receptor 1 (σR1) is expressed abundantly in the eye, and several reports suggest that this putative molecular chaperone plays a role in lens cell survival, control of intraocular pressure (IOP), and retinal neuroprotection. The present study examined the consequence of the absence of σR1 on ocular development, structure, and function. Methods. Wild-type (σR1 +/+), heterozygous (σR1 +/-), and homozygous (σR1 -/-, knockout) mice aged 5 to 59 weeks were subjected to comprehensive electrophysiological testing and IOP measurement. The eyes were examined by light and electron microscopy and subjected to morphometric examination and detection of apoptosis. Results. Cornea and lens of σR1 -/- mice were similar to wild-type mice in morphologic appearance at all ages examined, and IOP was within normal limits. Comprehensive ERG and morphometric analyses initially yielded normal findings in the σR1 -/- mice compared with those in the wild-type. By 12 months, however, significantly decreased ERG b-wave amplitudes and diminished negative scotopic threshold responses, consistent with inner retinal dysfunction, were detected in σR1 -/- mice. Concomitant with these late-onset changes were increased TUNEL- and active caspase 3-positive cells in the inner retina and significant loss of cells in the ganglion cell layer, particularly in the central retina. Before these functional and structural abnormalities, there was ultrastructural evidence of axonal disruption in the optic nerve head of σR1 -/- mice as early as 6 months of age, although there were no alterations observed in retinal vascularization in σR1 -/- mice. Conclusions. These data suggest that lack of σR1 leads to development of late-onset retinal dysfunction with similarities to optic neuropathy.

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