Correction of amblyopia in cats and mice after the critical period
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Evaluation Summary:
This study reports that monocular inactivation of the fellow (good) eye with tetrodotoxin supports long-lasting recovery from the effects of monocular deprivation, as measured by visual evoked potentials in primary visual cortex. This work should be of interest to neuroscientists studying plasticity and clinicians treating amblyopia. The results are compelling, although the advance compared to previous work is incremental.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
Monocular deprivation early in development causes amblyopia, a severe visual impairment. Prognosis is poor if therapy is initiated after an early critical period. However, clinical observations have shown that recovery from amblyopia can occur later in life when the non-deprived (fellow) eye is removed. The traditional interpretation of this finding is that vision is improved simply by the elimination of interocular suppression in primary visual cortex, revealing responses to previously subthreshold input. However, an alternative explanation is that silencing activity in the fellow eye establishes conditions in visual cortex that enable the weak connections from the amblyopic eye to gain strength, in which case the recovery would persist even if vision is restored in the fellow eye. Consistent with this idea, we show here in cats and mice that temporary inactivation of the fellow eye is sufficient to promote a full and enduring recovery from amblyopia at ages when conventional treatments fail. Thus, connections serving the amblyopic eye are capable of substantial plasticity beyond the critical period, and this potential is unleashed by reversibly silencing the fellow eye.
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Author Response:
Evaluation Summary:
This study reports that monocular inactivation of the fellow (good) eye with tetrodotoxin supports long-lasting recovery from the effects of monocular deprivation, as measured by visual evoked potentials in primary visual cortex. This work should be of interest to neuroscientists studying plasticity and clinicians treating amblyopia. The results are compelling, although the advance compared to previous work is incremental.
We thank the reviewers for their positive assessment of the data and the constructive comments. We believe that the current study substantially advances knowledge over the current state of the art. Decades of previous experience in cats, monkeys and humans led to the conclusion that monocular occlusion therapy is no longer effective in producing a lasting improvement after the …
Author Response:
Evaluation Summary:
This study reports that monocular inactivation of the fellow (good) eye with tetrodotoxin supports long-lasting recovery from the effects of monocular deprivation, as measured by visual evoked potentials in primary visual cortex. This work should be of interest to neuroscientists studying plasticity and clinicians treating amblyopia. The results are compelling, although the advance compared to previous work is incremental.
We thank the reviewers for their positive assessment of the data and the constructive comments. We believe that the current study substantially advances knowledge over the current state of the art. Decades of previous experience in cats, monkeys and humans led to the conclusion that monocular occlusion therapy is no longer effective in producing a lasting improvement after the critical period, which we now also confirm in mice. The key finding of our study is that this conclusion does not apply if the fellow eye is temporarily inactivated, underscoring the critical difference between degrading image formation in one eye (by, e.g., patching) and temporarily silencing all retinal ganglion cell activity. Although our previous research showed that binocular inactivation can also promote recovery, the finding that this recovery is enabled by inactivating only one eye halves concern over ocular health following treatment and forces a revision in how earlier observations of the effects of enucleation of the fellow eye are interpreted. In addition and of particular significance, the effects of unilateral retinal inactivation promoting stable recovery from deprivation amblyopia were observed in both cats and mice, suggesting evolutionary conservation of a core mechanism for recovery of cortical function.
Reviewer #1:
In this manuscript, Fong et al. showed that temporary inactivation of the fellow (good) eye through injection of tetrodotoxin (TTX) led to long-lasting recovering from amblyopia beyond the critical period, using both mice and cats as model systems. In contrast, reverse occlusion only had short term effects. This work is built on previous works from the authors, showing that TTX injection did not have any obvious effects on neuronal health (DiCostanzo et al., 2020), and that reverse occlusion in cats induced anatomical recovery from amblyopia (Duffy et al., 2018). In summary, this work is clearly written, with a strong and simple message, and has potentially important clinical implications for the treatment of amblyopia. It could be significantly strengthened by some probing into potential mechanisms, especially whether mechanisms previously shown to be important for critical period plasticity are activated following temporary inactivation of the fellow eye. These may give insight into potential treatment strategies.
We share the reviewer's interest in mechanisms underlying recovery and look forward to investigating them in future studies. As it stands now, however, our work immediately suggests a strategy that could be reduced to practice, even before the mechanism is pinpointed.
Reviewer #2:
This manuscript by Fong and colleagues explores plasticity of circuits in the visual cortex of normally reared and amblyopic mice and cats. Previous work from this group had reported the exciting finding that transient inactivation of the non-deprived eye by intraocular injection of TTX can trigger substantial recovery of acuity in the deprived eye. Here the authors perform electrophysiological experiments to reveal that:
- Temporary inactivation of one eye in normally reared mice increases the visually evoke potential amplitude of the non-inactivated eye for more than 7 days
- Recovery of amblyopia from long term monocular deprivation is possible even in the adult
- Recovery is detectable even after 1 day of transient inactivation
- Recovery persists for a longer period of time than the recovery traditionally observed with reverse occlusion
- Inactivation has similar effects in mice and cat
The experiments described in this manuscript are generally carefully performed and results are very clear. The information gained from this study are important in advancing our understanding of adult plasticity and the potential to reverse amblyopia. This reviewer has a few questions/comments about the interpretation of the data that should be addressed to improve the impact and clarity of this study.
We appreciate the careful review of our manuscript. We hope we have addressed the reviewer’s questions and comments in our response to the editor’s summary above.
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Evaluation Summary:
This study reports that monocular inactivation of the fellow (good) eye with tetrodotoxin supports long-lasting recovery from the effects of monocular deprivation, as measured by visual evoked potentials in primary visual cortex. This work should be of interest to neuroscientists studying plasticity and clinicians treating amblyopia. The results are compelling, although the advance compared to previous work is incremental.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
In this manuscript, Fong et al. showed that temporary inactivation of the fellow (good) eye through injection of tetrodotoxin (TTX) led to long-lasting recovering from amblyopia beyond the critical period, using both mice and cats as model systems. In contrast, reverse occlusion only had short term effects. This work is built on previous works from the authors, showing that TTX injection did not have any obvious effects on neuronal health (DiCostanzo et al., 2020), and that reverse occlusion in cats induced anatomical recovery from amblyopia (Duffy et al., 2018). In summary, this work is clearly written, with a strong and simple message, and has potentially important clinical implications for the treatment of amblyopia. It could be significantly strengthened by some probing into potential mechanisms, …
Reviewer #1 (Public Review):
In this manuscript, Fong et al. showed that temporary inactivation of the fellow (good) eye through injection of tetrodotoxin (TTX) led to long-lasting recovering from amblyopia beyond the critical period, using both mice and cats as model systems. In contrast, reverse occlusion only had short term effects. This work is built on previous works from the authors, showing that TTX injection did not have any obvious effects on neuronal health (DiCostanzo et al., 2020), and that reverse occlusion in cats induced anatomical recovery from amblyopia (Duffy et al., 2018). In summary, this work is clearly written, with a strong and simple message, and has potentially important clinical implications for the treatment of amblyopia. It could be significantly strengthened by some probing into potential mechanisms, especially whether mechanisms previously shown to be important for critical period plasticity are activated following temporary inactivation of the fellow eye. These may give insight into potential treatment strategies.
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Reviewer #2 (Public Review):
This manuscript by Fong and colleagues explores plasticity of circuits in the visual cortex of normally reared and amblyopic mice and cats. Previous work from this group had reported the exciting finding that transient inactivation of the non-deprived eye by intraocular injection of TTX can trigger substantial recovery of acuity in the deprived eye. Here the authors perform electrophysiological experiments to reveal that:
1. Temporary inactivation of one eye in normally reared mice increases the visually evoke potential amplitude of the non-inactivated eye for more than 7 days
2. Recovery of amblyopia from long term monocular deprivation is possible even in the adult
3. Recovery is detectable even after 1 day of transient inactivation
4. Recovery persists for a longer period of time than the recovery …Reviewer #2 (Public Review):
This manuscript by Fong and colleagues explores plasticity of circuits in the visual cortex of normally reared and amblyopic mice and cats. Previous work from this group had reported the exciting finding that transient inactivation of the non-deprived eye by intraocular injection of TTX can trigger substantial recovery of acuity in the deprived eye. Here the authors perform electrophysiological experiments to reveal that:
1. Temporary inactivation of one eye in normally reared mice increases the visually evoke potential amplitude of the non-inactivated eye for more than 7 days
2. Recovery of amblyopia from long term monocular deprivation is possible even in the adult
3. Recovery is detectable even after 1 day of transient inactivation
4. Recovery persists for a longer period of time than the recovery traditionally observed with reverse occlusion
5. Inactivation has similar effects in mice and catThe experiments described in this manuscript are generally carefully performed and results are very clear. The information gained from this study are important in advancing our understanding of adult plasticity and the potential to reverse amblyopia. This reviewer has a few questions/comments about the interpretation of the data that should be addressed to improve the impact and clarity of this study.
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