Rapid recovery from the effects of early monocular deprivation is enabled by temporary inactivation of the retinas

Abstract

A half-century of research on the consequences of monocular deprivation (MD) in animals has revealed a great deal about the pathophysiology of amblyopia. MD initiates synaptic changes in the visual cortex that reduce acuity and binocular vision by causing neurons to lose responsiveness to the deprived eye. However, much less is known about how deprivation-induced synaptic modifications can be reversed to restore normal visual function. One theoretically motivated hypothesis is that a period of inactivity can reduce the threshold for synaptic potentiation such that subsequent visual experience promotes synaptic strengthening and increased responsiveness in the visual cortex. Here we have reduced this idea to practice in two species. In young mice, we show that the otherwise stable loss of cortical responsiveness caused by MD is reversed when binocular visual experience follows temporary anesthetic inactivation of the retinas. In 3-mo-old kittens, we show that a severe impairment of visual acuity is also fully reversed by binocular experience following treatment and, further, that prolonged retinal inactivation alone can erase anatomical consequences of MD. We conclude that temporary retinal inactivation represents a highly efficacious means to promote recovery of function. A mblyopia is a widespread form of human visual disability that arises from imbalanced visual experience in the two eyes during infancy or early childhood. The core pathophysiological process underlying amblyopia is ocular dominance plasticity in the primary visual cortex (V1). Ocular dominance plasticity, evolutionarily conserved in mammals with binocular vision, has become a classic paradigm for studying how brain development is influenced by experience and deprivation. A brief period of monocular deprivation (MD) during early postnatal life causes functional depression of synapses in V1 that serve the deprived eye (1-7). Consequently, early-life MD severely and persistently degrades visual acuity through the deprived eye, which typically fails to recover spontaneously when binocular vision is restored (8-10). A critical step in developing targeted interventions for treating amblyopia is to identify strategies for reversing deprivation-driven synaptic modifications in V1.The traditional approach to promote recovery following MD has been to occlude the strong eye to force vision through the weak amblyopic eye. This "reverse occlusion" approach has been validated in animals (11, 12) and represents the cornerstone of current treatment (patching therapy) of human amblyopia (13-16). However, this treatment has well-known limitations that include poor compliance, potential loss of vision through the newly patched eye, failure to recover binocular vision, and a declining treatment efficacy with age (15, 17-21). Nevertheless, the success of reverse occlusion strategies demonstrates that severely weakened synaptic inputs in the brain can be rejuvenated under appropriate circumstances.An insight into how reverse occlusion might promote recovery came fr...

Recovery from the anatomical effects of long‐term monocular deprivation in cat lateral geniculate nucleus

“…Subsequent TTX injections were made every 48 hr using the original injection site so as to avoid having to make an additional puncture. A single dose of intravitreal TTX has been shown to effectively eliminate visual responses for at least 48 hr (Stryker & Harris, ; Linden, Heynen, Haslinger, & Bear, ; Fong et al, ). All animals that received binocular or monocular TTX injections had their deprived eye opened prior to the first intravitreal injection, and the same injection procedure was followed for both groups.…”

“…Binocular retinal inactivation with intravitreal TTX injection has recently been shown to promote both anatomical and behavioral recovery from 1 week of MD in kittens (Fong et al, ) so we examined the ability for this treatment to promote recovery from 6 weeks of MD. TTX is a voltage‐gated sodium channel blocker that when injected into the posterior chamber of the eye temporarily abolishes retinal ganglion activity for at least 48 hr (Stryker & Harris, ; Linden et al, ; Fong et al, ). Binocular inactivation of retinal ganglion cells for 10 days following 6 weeks of MD stimulated about 50% recovery, leaving deprived neurons still significantly smaller than non‐deprived neurons by an average of 17% ( U = 0, p = .028; Figure c1–3).…”

“…Notwithstanding this notable recovery, neuron somata within deprived layers were still significantly smaller than those within non‐deprived layers after providing binocular vision ( U = 4, p = .026) or reverse occlusion ( U = 0, p = .028). Binocular retinal inactivation with intravitreal TTX injection has recently been shown to promote both anatomical and behavioral recovery from 1 week of MD in kittens (Fong et al, ) so we examined the ability for this treatment to promote recovery from 6 weeks of MD. TTX is a voltage‐gated sodium channel blocker that when injected into the posterior chamber of the eye temporarily abolishes retinal ganglion activity for at least 48 hr (Stryker & Harris, ; Linden et al, ; Fong et al, ).…”

“…However, in young kittens subjected to 1 week of MD at the critical period peak, 10 days of dark exposure stimulated full recovery of deprived‐eye neuron soma size in the dLGN (O'Leary, Kutcher, Mitchell, & Duffy, ; Duffy, Bukhamseen, Smithen, & Mitchell, ), and led to a rapid and complete recovery from amblyopia (Duffy & Mitchell, ; Duffy et al, ; Mitchell, MacNeil, Crowder, Holman, & Duffy, ). More recently, temporary elimination of visually‐driven activity through binocular retinal inactivation erased the anatomical and acuity deficits in kittens subjected to one week of MD at the peak of the critical period (Fong, Mitchell, Duffy, & Bear, ). A possible explanation for the observed recovery following darkness and binocular retinal inactivation is that attenuation of neural activity alters the threshold for synaptic plasticity (Kirkwood, Rioult, & Bear, ; Cooper & Bear, ), setting the stage for recovery of normal visual acuity after binocular vision is restored.…”

Amblyopia: New molecular/pharmacological and environmental approaches

“…Thus, access to completely dark environments for a sufficient duration of time with proper support to guarantee safety and well-being may pose challenges for widespread use. Interestingly, visual deprivation for several days by binocular intravitreal injections of the pufferfish toxin tetrodotoxin promotes similar fast visual recovery in amblyopic cats (Fong et al, 2016), raising the possibility of developing novel pharmacological techniques to transiently block vision, if adequate safety measures can reliably be ensured. Blindfolding may offer another solution—one study suggested that blindfolding normally sighted adults for 5 days leads to rapid changes in experience-dependent functional neural connectivity (Merabet et al, 2008).…”