Rapid Recovery from the Effects of Early Monocular Deprivation Is Enabled by Temporary Inactivation of the Retinas
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Rapid recovery from the effects of early monocular deprivation is enabled by temporary inactivation of the retinas Ming-fai Fonga, Donald E. Mitchellb, Kevin R. Duffyb, and Mark F. Beara,1 aPicower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; and bDepartment of Psychology and Neuroscience, Dalhousie University, Halifax, NS, Canada B3H 4R2 Edited by Robert C. Malenka, Stanford University School of Medicine, Stanford, CA, and approved October 17, 2016 (received for review August 9, 2016) A half-century of research on the consequences of monocular An insight into how reverse occlusion might promote recovery deprivation (MD) in animals has revealed a great deal about the came from a study in cat V1, which showed that neurons lose pathophysiology of amblyopia. MD initiates synaptic changes in responsiveness to the newly occluded eye days before gaining the visual cortex that reduce acuity and binocular vision by causing responses to the newly open (amblyopic) eye (22). It is now neurons to lose responsiveness to the deprived eye. However, much understood that the qualities of cortical synaptic plasticity de- less is known about how deprivation-induced synaptic modifications pend on the recent history of cortical activity, a property called can be reversed to restore normal visual function. One theoreti- metaplasticity (23). After a period of attenuated cortical activity, cally motivated hypothesis is that a period of inactivity can reduce the threshold for synaptic potentiation is reduced (24–26). Thus, the threshold for synaptic potentiation such that subsequent the period of quiescence that immediately follows initiation of visual experience promotes synaptic strengthening and increased reverse occlusion lowers the threshold for synaptic potentiation, responsiveness in the visual cortex. Here we have reduced this enabling subsequent visual experience to increase synaptic ef- idea to practice in two species. In young mice, we show that the fectiveness when it would have otherwise been without effect otherwise stable loss of cortical responsiveness caused by MD is (27). An intriguing possibility is that imposition of a period of reversed when binocular visual experience follows temporary binocular inactivity following early MD could be sufficient to anesthetic inactivation of the retinas. In 3-mo-old kittens, we show promote visual recovery without forcing the eyes to compete. that a severe impairment of visual acuity is also fully reversed by In support of this concept, studies have shown that exposure binocular experience following treatment and, further, that pro- of adult rats and kittens to a period of continuous darkness can longed retinal inactivation alone can erase anatomical conse- prime the visual cortex for recovery from the effect of MD when vision is restored to the deprived eye (28–30). However, avail- quences of MD. We conclude that temporary retinal inactivation ≥ represents a highly efficacious means to promote recovery of function. able data suggest that this priming effect requires 10 d of darkness, which cannot be interrupted, even briefly, by light exposure and cannot be substituted with binocular lid closure ocular dominance plasticity | metaplasticity | amblyopia | visual cortex | NEUROSCIENCE (31, 32). Further, work in kittens has shown that when initiated lateral geniculate nucleus before 10 wk of age, exposure to total darkness itself can cause temporary visual impairment and even blindness before 7 wk of mblyopia is a widespread form of human visual disability age (33). Thus, although these results show the potential of Athat arises from imbalanced visual experience in the two using insights gained from the study of synaptic plasticity to eyes during infancy or early childhood. The core pathophysio- promote recovery of function (34), application of this approach logical process underlying amblyopia is ocular dominance plas- to clinical practice presents many challenges. ticity in the primary visual cortex (V1). Ocular dominance plasticity, evolutionarily conserved in mammals with binocular Significance vision, has become a classic paradigm for studying how brain development is influenced by experience and deprivation. A Normal development of the visual cortex depends critically on brief period of monocular deprivation (MD) during early post- early life visual experience. In humans, a disparity in the quality natal life causes functional depression of synapses in V1 that of vision between two eyes during infancy or early childhood serve the deprived eye (1–7). Consequently, early-life MD se- leads to a visual impairment called amblyopia. In animal models, verely and persistently degrades visual acuity through the de- amblyopia can be induced early in life using a brief period of prived eye, which typically fails to recover spontaneously when monocular deprivation via eyelid closure. Here we show in two binocular vision is restored (8–10). A critical step in develop- evolutionarily divergent species that experimental amblyopia ing targeted interventions for treating amblyopia is to identify can be rapidly corrected if binocular visual experience is restored strategies for reversing deprivation-driven synaptic modifications after temporarily silencing the retinas with a local anesthetic. in V1. These findings point the way to an approach for clinical man- The traditional approach to promote recovery following MD agement of amblyopia with advantages over the current stan- has been to occlude the strong eye to force vision through the dard of care. weak amblyopic eye. This “reverse occlusion” approach has been Author contributions: M.-f.F., D.E.M., K.R.D., and M.F.B. designed research; M.-f.F., D.E.M., validated in animals (11, 12) and represents the cornerstone of and K.R.D. performed research; M.-f.F., D.E.M., K.R.D., and M.F.B. analyzed data; and M.-f.F., current treatment (patching therapy) of human amblyopia (13– D.E.M., K.R.D., and M.F.B. wrote the paper. 16). However, this treatment has well-known limitations that Conflict of interest statement: The authors disclose a patent filing on the use of retinal include poor compliance, potential loss of vision through the inactivation to treat human amblyopia. newly patched eye, failure to recover binocular vision, and a This article is a PNAS Direct Submission. declining treatment efficacy with age (15, 17–21). Nevertheless, Freely available online through the PNAS open access option. the success of reverse occlusion strategies demonstrates that se- 1To whom correspondence should be addressed. Email: [email protected]. verely weakened synaptic inputs in the brain can be rejuvenated This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. under appropriate circumstances. 1073/pnas.1613279113/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1613279113 PNAS | December 6, 2016 | vol. 113 | no. 49 | 14139–14144 Downloaded by guest on October 1, 2021 In the current study, we set out to examine an alternative remained significantly reduced after 1 wk and 1 mo of binoc- method involving temporary anesthetic inactivation of the ular visual experience following MD, compared with pre-MD retinas. For decades, researchers of visual system develop- baseline values (Fig. 1D, Center;1wk:P = 0.0246; 1 mo: P = ment have used tetrodotoxin (TTX) to investigate the con- 0.0023) and to sham littermate controls (Fig. 1D, Left;1wk: sequences of blocking action potentials in retinal ganglion P = 0.0020; 1 mo: P = 0.0204). The sustained depression of cells. A single dose, administered by microinjection into the deprived-eye responses was also observed at lower and higher vitreous humor, can locally block all impulse activity in the spatial frequencies (Fig. S1). These results demonstrate that optic nerve for a day or two. Of significance, inactivation of the visual deficit observed after 7 d of MD is long lasting and further one eye with TTX fails to trigger depression of deprived-eye validate the mouse as a useful animal model of amblyopia. responses in V1 that is observed after comparable periods of monocular deprivation by lid closure or image blurring (5, 7, Temporary Retinal Inactivation Promotes Electrophysiological 35–37). Thus, brief inactivation of both eyes with TTX could Recovery in Amblyopic Mice. After confirming depression of de- potentially augment recovery of function by lowering the plas- prived-eye VEP magnitude immediately following 7-d MD (Fig. ticity threshold without the liability associated with other forms 1D, Right; P = 0.0099; 0.2 cpd), a cohort of mice received a of deprivation. Furthermore, because the retinas are silent until binocular intravitreal TTX injection, eliminating retinal activity the drug wears off, compliance is assured. for ∼2 d, followed by normal binocular experience. Subsequent To test this hypothesis, we performed parallel studies in VEP recordings revealed responses to the deprived eye that mice and kittens. Our interest in mice was driven by the utility actually exceeded baseline values 1 wk later (P = 0.0562) and of this species for mechanistic studies. Although the imme- were no different from baseline 1 mo later (P = 0.9454). Visually diate effects of MD in mice have been well documented, less evoked responses in animals that experienced binocular in- was known about the stability of these effects. Therefore, we activation following MD were significantly increased over lit- first conducted a longitudinal