September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Insulin stimulates retinal ganglion cell dendrite regeneration through activation of the mammalian target of rapamycin complex 1and complex 2
Author Affiliations & Notes
  • Jessica Agostinone
    Neurosciences, Centre de recherche du CHUM, Montreal, Quebec, Canada
    Neurosciences, Université de Montréal, Montréal, Quebec, Canada
  • Adriana Di Polo
    Neurosciences, Centre de recherche du CHUM, Montreal, Quebec, Canada
    Neurosciences, Université de Montréal, Montréal, Quebec, Canada
  • Footnotes
    Commercial Relationships   Jessica Agostinone, None; Adriana Di Polo, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      Jessica Agostinone, Adriana Di Polo; Insulin stimulates retinal ganglion cell dendrite regeneration through activation of the mammalian target of rapamycin complex 1and complex 2. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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

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Abstract

Purpose : Emerging data indicate that axonal injury triggers rapid structural alterations in retinal ganglion cell (RGC) dendrites, which might contribute to neurodegeneration in glaucoma. We recently demonstrated that the mammalian target of rapamycin complex 1 (mTORC1) plays a key role in RGC dendrite stability. The purpose of this study was to: 1) determine whether RGC dendrites, once retracted, can regenerate to pre-injury length, surface area and complexity; and 2) establish whether mTORC1 activation is sufficient to stimulate RGC dendrite regeneration.

Methods : Optic nerve axotomy was performed in transgenic mice expressing yellow fluorescent protein (YFP) specifically in RGCs. Insulin, a potent activator of both mTORC1 and mTORC2, was administered daily starting at three days after axotomy, when RGC dendrites have already retracted. The following compounds were administered by systemic or intravitreal injection: i) rapamycin, a specific inhibitor of mTORC1; ii) siRNA against Rictor, an essential component of mTORC2 activity; iii)KU0063794, an inhibitor of mTORC1/2. Seven days post-injury, RGC dendritic trees were 3D-reconstructed and analyzed.RGC survival was assessed by quantification of RBPMS-labeled cells.

Results : Our data show that insulin, administered systemically or topically as eye drops, promoted remarkable dendrite regeneration and restored branch length, complexity and field area to values similar to those in non-injured RGCs (N=4-6/group, 28-48 RGCs/group). Administration of insulin with rapamycin, which blocked only mTORC1, resulted in loss of dendritic tree complexity, while length and field area were preserved. In contrast, combined insulin and siRictor, which blocked only mTORC2, resulted in loss of dendritic length and field area but did not alter complexity. KU0063794, which inhibited both complexes, completely abrogated dendrite regeneration. Insulin-mediated RGC survival depended on both mTORC1 and mTORC2 activity.

Conclusions : This study demonstrates that insulin promotes substantial RGC dendrite regeneration after axonal injury. Our data show that both complexes are required for successful dendritic regeneration, with mTORC1controlling tree complexity and mTORC2 governing dendrite length and arbor area. The ability to regenerate dendrites in injured RGCs may have implications to prevent synaptic loss and visual deficits in glaucoma

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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