Metaplasticity: a key to visual recovery from amblyopia in adulthood?

Abstract

Purpose of reviewWe examine the development of amblyopia and the effectiveness of conventional and emerging therapies through the lens of the Bienenstock, Cooper, and Munro (BCM) theory of synaptic modification.Recent findingsThe BCM theory posits metaplastic adjustment in the threshold for synaptic potentiation, governed by prior neuronal activity. Viewing established clinical principles of amblyopia treatment from the perspective of the BCM theory, occlusion, blur, or release of interocular suppression reduce visual cortical activity in the amblyopic state to lower the modification threshold and enable amblyopic eye strengthening. Although efficacy of these treatment approaches declines with age, significant loss of vision in the fellow eye by damage or disease can trigger visual acuity improvements in the amblyopic eye of adults. Likewise, reversible retinal inactivation stimulates recovery of amblyopic eye visual function in adult mice and cats.SummaryConventional and emerging amblyopia treatment responses abide by the framework of BCM theory. Preclinical studies support that the dramatic reduction in cortical activity accompanying temporary retinal silencing can promote recovery from amblyopia even in adulthood, highlighting a promising therapeutic avenue.

Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome

“…5 ). Similarly, the aberrant recruitment of LTD before training may lead, not to its saturation per se , but to some other kind of reduced availability, such as an increased threshold for its induction (Bienenstock, Cooper, and Munro, 1982; Leet, Bear, and Gaier, 2022). This saturation or increased threshold hypothesis differs from the over-recruitment hypothesis by suggesting that LTD is under-rather than over-recruited during the training period in mice with enhanced LTD, and that the problem with enhanced LTD arises because of what it does to the circuit before training, rather than how it functions during training.…”

“…5 ). Nguyen-Vu and colleagues (2017) described this reduced availability as saturation of plasticity, but more generally, the reduced availability could reflect an increased threshold for the induction plasticity (Bienenstock, Cooper, and Munro, 1982; Leet, Bear, and Gaier, 2022). This threshold metaplasticity hypothesis differs from the over-recruitment hypothesis by suggesting that the enhanced plasticity mechanism is under- rather than over- recruited during training.…”

Recovery from Amblyopia in Adulthood: A Meta-Analysis

“…There is extensive evidence that at least partial recovery from amblyopia can occur in experimental animal models late in the critical period (when simple occlusiontype interventions fail) and beyond [11][12][13][14] . For instance, experiments in mice and cats show that temporary inactivation of retinal ganglion cell (RGC) activity in both eyes or just the FE establishes conditions that enable the rapid and durable recovery from amblyopia [15][16][17] .…”

Comments on: Partial Recovery of Amblyopia After Fellow Eye Ischemic Optic Neuropathy: Response

“…Restoration of cortical activity driven through the AE (as enabled through metaplastic change) would confer a relatively high threshold for synaptic plasticity and maintain ocular dominance at that new baseline. 2 Therefore, we would expect that the clinical gains in AEVA observed after temporary or partially reversible FE pathology would also be durable. Future clinical studies focused on completely reversible FE pathologies may be informative in this regard.…”

“…1 As Dr. Örnek points out, there are several potential mechanisms at play as we have outlined in a recent review. 2 We are committed to elucidating these mechanisms which hold translational potential for visual recovery beyond amblyopia.…”