Amblyopia: New molecular/pharmacological and environmental approaches

Abstract

Emerging technologies are now giving us unprecedented access to manipulate brain circuits, shedding new light on treatments for amblyopia. This research is identifying key circuit elements that control brain plasticity and highlight potential therapeutic targets to promote rewiring in the visual system during and beyond early life. Here, we explore how such recent advancements may guide future pharmacological, genetic, and behavioral approaches to treat amblyopia. We will discuss how animal research, which allows us to probe and tap into the underlying circuit and synaptic mechanisms, should best be used to guide therapeutic strategies. Uncovering cellular and molecular pathways that can be safely targeted to promote recovery may pave the way for effective new amblyopia treatments across the lifespan.

Keywords: Critical period; Dark exposure; E/I balance; Environmental enrichment; Light deprivation; Monocular deprivation; Neuromodulatory systems.

Fig. 1.

Cellular and circuit mechanisms underlying molecular, pharmacological, and environmental approaches to increase plasticity in the visual cortex. Release of neuromodulators in the visual cortex, such as acetylcholine (ACh) or serotonin (5-HT = 5-hydroxytryptophan), activate VIP (vasoactive intestinal polypeptide) inhibitory cells that promote cortical activity and plasticity by inhibiting other inhibitory interneuron subtypes, PV (parvalbumin), and SOM (somatostatin) cells (Letzkus et al., 2011; Pi et al., 2013; Fu et al., 2014; Kaneko & Stryker, 2014; Fu et al., 2015). These neuromodulatory systems can be activated by pharmacological treatments such as cholinesterase (AChE) inhibitors (Morishita et al., 2010) or selective serotonin reuptake inhibitors (SSRIs; Maya Vetencourt et al., 2008; Thompson et al., 2014) or behavioral therapies such as exercise (Fu et al., 2015; Lunghi & Sale, 2015) and video game training (Bavelier et al., 2010). Transplantation of embryonic inhibitory neurons into the postnatal visual cortex induces a second critical period of OD plasticity after the normal one (Southwell et al., 2010; Tang et al., 2014; Isstas et al., 2017). Plasticity is also enhanced in the adult visual cortex by decreasing perineuronal nets that predominantly enwrap the PV cells by pharmacological (Pizzorusso et al., 2002) or behavioral interventions, such as environmental enrichment (Sale et al., 2007) or dark exposure (Stodieck et al., 2014). A reduction in the excitatory drive to PV cells (Huang et al., 2010; Gu et al., 2016) and an increase in spine density and NMDA-Rs (Yashiro et al., 2005; He et al., 2006; Philpot et al., 2007; Montey & Quinlan, 2011) may also contribute to the enhanced plasticity that occurs with dark exposure. Various manipulations that reduce inhibitory synaptic function have been found to enhance visual cortical plasticity, including drugs that inhibit GABA synthesis or GABA_A receptors (Harauzov et al., 2010), tDCS/TMS (Stagg et al., 2009), and environmental enrichment (Greifzu et al., 2014). Inhibition of HDACs can also reinstate plasticity in the adult visual cortex to allow recovery from amblyopia (Putignano et al., 2007; Silingardi et al., 2010). Finally, an increase in AMPA-silent synapses (white synaptic boutons) underlies the heightened plasticity following knock-out or virus-mediated gene silencing of PSD-95 (Huang et al., 2015). Silent synapses also persist in the adult visual cortex in dark-reared mice (Funahashi et al., 2013). The figure is modified from the one presented by Takao Hensch at the Lasker/IRRF Initiative on Amblyopia workshops. Woods Hole, MA, July/August, 2015.