Correction of amblyopia in cats and mice after the critical period

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.

Comparative analysis of structural modifications induced by monocular retinal inactivation and monocular deprivation in the developing cat lateral geniculate nucleus

“…The reduction of VEP power elicited through the inactivated eye recovered following 10 days of binocular vision and was not different from VEP power measured before inactivation was imposed (multiple comparisons post‐hoc test: p = 0.639). It is worth pointing out that the restoration of normal dLGN soma size and the recovery of VEPs after inactivation occurred at an age (i.e., 10 weeks old) when inactivation of the fellow eye can promote full recovery from the anatomical and physiological effects of long‐term MD (Duffy et al., 2018; Fong et al., 2021). The current findings indicate that the modifications elicited by inactivation do not have a lasting negative impact on the structure or function of the visual system, and instead appear to elicit a constellation of modifications that avail an opportunity for recovery from the neural modifications produced by amblyogenic rearing.…”

“…Just as an inactive muscle fiber rapidly recovers size when the temporarily silenced motoneuron activity is restored, we next sought to understand if dLGN cell size changes ascribed to reduced retinal activity is similarly transient and reversible. In previous studies, we demonstrated that fellow-eye retinal inactivation applied at 10 weeks of age can promote recovery from the effects of a prior long-term MD, and critically the inactivation produced no lasting detriment to the inactivated eye or to the dLGN layers connected to it (DiCostanzo et al, 2020;Duffy et al, 2018;Fong et al, 2021). We therefore examined reversibility of retinal inactivation on dLGN cell size changes by providing a subset of animals with binocular vision (10 days) after they received 10 days of retinal inactivation applied at 10 weeks of age.…”

“…Following a long‐term MD in which ocular dominance is shifted strongly in favor of the non‐deprived eye, inactivation of the stronger eye in both mice and cats can promote recovery of visually driven cortical responses elicited by the weaker eye (Fong et al., 2021). Similar recovery occurs in the cat dLGN, where deprived neurons rendered smaller by MD recover to their normal size when the non‐deprived eye is inactivated for 10 days (Duffy et al., 2018).…”

“…Recent mouse and cat studies have demonstrated that post‐critical period recovery from MD can occur if the dominant eye's retina is temporarily inactivated with intravitreal microinjection of tetrodotoxin (TTX), a voltage‐gated sodium channel blocker that can reversibly eliminate retinal ganglion cell activity (Duffy et al., 2018; Fong et al., 2021). Following a period of MD, inactivation of the dominant (fellow) eye restores neural responses to the weaker one and promotes recovery from the MD‐induced atrophy of neuron soma size in the dLGN.…”

Visual experience has opposing influences on the quality of stimulus representation in adult primary visual cortex

“…Depression of deprived inputs occurs at a synaptic level and outlasts the perturbation. On the other hand, the same peripheral perturbation in adults does not induce a rapid decrease in response strength, although potentiation of the intact input does proceed ( Fong et al, 2021 ; Jenks et al, 2017 ). Furthermore, in the young, the impact of deprivation on excitatory neuron activity levels is compensated for by a decrease in evoked inhibitory neuron activity.…”