Amblyopia: New molecular/pharmacological and environmental approaches.

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.

[1]  E. Engle,et al.  Genetic basis of congenital strabismus. , 2007, Archives of ophthalmology.

[2]  Mriganka Sur,et al.  Nucleus basalis-enabled stimulus-specific plasticity in the visual cortex is mediated by astrocytes , 2012, Proceedings of the National Academy of Sciences.

[3]  E. Quinlan,et al.  Experience-dependent recovery of vision following chronic deprivation amblyopia , 2007, Nature Neuroscience.

[4]  R. Douglas,et al.  Characterization of mouse cortical spatial vision , 2004, Vision Research.

[5]  M. Perdziak,et al.  Not only amblyopic but also dominant eye in subjects with strabismus show increased saccadic latency. , 2016, Journal of vision.

[6]  Daphne Bavelier,et al.  A dichoptic custom-made action video game as a treatment for adult amblyopia , 2015, Vision Research.

[7]  Rebekah J. Corlew,et al.  Visual Deprivation Modifies Both Presynaptic Glutamate Release and the Composition of Perisynaptic/Extrasynaptic NMDA Receptors in Adult Visual Cortex , 2005, The Journal of Neuroscience.

[8]  H. Goltz,et al.  Effects of strabismic amblyopia and strabismus without amblyopia on visuomotor behavior, I: saccadic eye movements. , 2012, Investigative ophthalmology & visual science.

[9]  J. Wood,et al.  Fine Motor Skills of Children With Amblyopia Improve Following Binocular Treatment. , 2016, Investigative ophthalmology & visual science.

[10]  Alessandro Sale,et al.  Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition , 2007, Nature Neuroscience.

[11]  Robert F. Hess,et al.  Amblyopia and the binocular approach to its therapy , 2015, Vision Research.

[12]  Dennis M. Levi,et al.  Hyperacuity and amblyopia , 1982, Nature.

[13]  Takao K Hensch,et al.  Balancing plasticity/stability across brain development. , 2013, Progress in brain research.

[14]  L. Kiorpes,et al.  "Global" visual training and extent of transfer in amblyopic macaque monkeys. , 2015, Journal of vision.

[15]  Johannes Burge,et al.  Binocular integration and disparity selectivity in mouse primary visual cortex. , 2013, Journal of neurophysiology.

[16]  Joshua I. Sanders,et al.  Cortical interneurons that specialize in disinhibitory control , 2013, Nature.

[17]  Michael P. Stryker,et al.  Anatomical Correlates of Functional Plasticity in Mouse Visual Cortex , 1999, The Journal of Neuroscience.

[18]  L. Maffei,et al.  Reactivation of Ocular Dominance Plasticity in the Adult Visual Cortex , 2002, Science.

[19]  Alessandro Sale,et al.  A cycling lane for brain rewiring , 2015, Current Biology.

[20]  Daniel P. Spiegel,et al.  The effect of transcranial direct current stimulation on contrast sensitivity and visual evoked potential amplitude in adults with amblyopia , 2016, Scientific Reports.

[21]  Howard C. Nusbaum,et al.  Auditory working memory predicts individual differences in absolute pitch learning , 2015, Cognition.

[22]  S. Löwel,et al.  Voluntary Physical Exercise Promotes Ocular Dominance Plasticity in Adult Mouse Primary Visual Cortex , 2014, The Journal of Neuroscience.

[23]  E. Quinlan,et al.  Recovery from chronic monocular deprivation following reactivation of thalamocortical plasticity by dark exposure. , 2011, Nature communications.

[24]  M. Stryker,et al.  Modulation of Visual Responses by Behavioral State in Mouse Visual Cortex , 2010, Neuron.

[25]  Michael P. Stryker,et al.  Report Tumor Necrosis Factor-a Mediates One Component of Competitive, Experience-dependent Plasticity in Developing Visual Cortex , 2022 .

[26]  Takao K. Hensch,et al.  Lynx1, a Cholinergic Brake, Limits Plasticity in Adult Visual Cortex , 2010, Science.

[27]  S. Löwel,et al.  Environmental enrichment preserved lifelong ocular dominance plasticity, but did not improve visual abilities , 2016, Neurobiology of Aging.

[28]  K. Fox,et al.  Dark-rearing delays the loss of NMDA-receptor function in kitten visual cortex , 1991, Nature.

[29]  Siegrid Löwel,et al.  Environmental enrichment extends ocular dominance plasticity into adulthood and protects from stroke-induced impairments of plasticity , 2014, Proceedings of the National Academy of Sciences.

[30]  Ewa Niechwiej-Szwedo,et al.  Abnormal visual experience during development alters the early stages of visual-tactile integration , 2016, Behavioural Brain Research.

[31]  Erhardt Barth,et al.  A novel measure to determine viewing priority and its neural correlates in the human brain. , 2016, Journal of vision.

[32]  E. Quinlan,et al.  Optimization of visual training for full recovery from severe amblyopia in adults , 2016, Learning & memory.

[33]  B. Godley,et al.  TWEAK/Fn14 pathway is a novel mediator of retinal neovascularization. , 2014, Investigative ophthalmology & visual science.

[34]  M. Stryker,et al.  Sensory experience during locomotion promotes recovery of function in adult visual cortex , 2014, eLife.

[35]  B. Wick,et al.  Anisometropic Amblyopia: Is the Patient Ever Too Old to Treat? , 1992, Optometry and vision science : official publication of the American Academy of Optometry.

[36]  B. Mansouri,et al.  Restoration of Binocular Vision in Amblyopia , 2011, Strabismus.

[37]  D. Melmoth,et al.  Eye-hand coordination skills in children with and without amblyopia. , 2011, Investigative ophthalmology & visual science.

[38]  M P Stryker,et al.  Rapid remodeling of axonal arbors in the visual cortex. , 1993, Science.

[39]  S. McKee,et al.  Saccadic latency in amblyopia , 2016, Journal of vision.

[40]  M. Cynader,et al.  Prolonged sensitivity to monocular deprivation in dark-reared cats: effects of age and visual exposure. , 1983, Brain research.

[41]  H. Goltz,et al.  Effects of anisometropic amblyopia on visuomotor behavior, I: saccadic eye movements. , 2010, Investigative ophthalmology & visual science.

[42]  L. Maffei,et al.  Developmental Downregulation of Histone Posttranslational Modifications Regulates Visual Cortical Plasticity , 2007, Neuron.

[43]  D. Mitchell,et al.  Rapid recovery from the effects of early monocular deprivation is enabled by temporary inactivation of the retinas , 2016, Proceedings of the National Academy of Sciences.

[44]  M. Steinbach,et al.  Eye position stability in amblyopia and in normal binocular vision. , 2012, Investigative ophthalmology & visual science.

[45]  Frances A Champagne,et al.  Epigenetic influences on brain development and plasticity , 2009, Current Opinion in Neurobiology.

[46]  Mark F. Bear,et al.  How Monocular Deprivation Shifts Ocular Dominance in Visual Cortex of Young Mice , 2004, Neuron.

[47]  Rana Arham Raashid,et al.  The Initiation of Smooth Pursuit is Delayed in Anisometropic Amblyopia , 2016, Investigative ophthalmology & visual science.

[48]  H. Goltz,et al.  Effects of strabismic amblyopia and strabismus without amblyopia on visuomotor behavior: III. Temporal eye-hand coordination during reaching. , 2014, Investigative ophthalmology & visual science.

[49]  Dennis M. Levi,et al.  Characteristics of fixational eye movements in amblyopia: Limitations on fixation stability and acuity? , 2015, Vision Research.

[50]  D. Mitchell,et al.  Binocular eyelid closure promotes anatomical but not behavioral recovery from monocular deprivation , 2015, Vision Research.

[51]  D. Levi,et al.  Central and peripheral contrast sensitivity in amblyopia with varying field size , 1984, Documenta Ophthalmologica.

[52]  T. Pizzorusso,et al.  Epigenetic treatments of adult rats promote recovery from visual acuity deficits induced by long‐term monocular deprivation , 2010, The European journal of neuroscience.

[53]  David C. Knill,et al.  Stereopsis and amblyopia: A mini-review , 2015, Vision Research.

[54]  Daphne Bavelier,et al.  Removing Brakes on Adult Brain Plasticity: From Molecular to Behavioral Interventions , 2010, The Journal of Neuroscience.

[55]  Naomi B. Pitskel,et al.  Rapid and Reversible Recruitment of Early Visual Cortex for Touch , 2008, PloS one.

[56]  M. Scanziani,et al.  Inhibition of Inhibition in Visual Cortex: The Logic of Connections Between Molecularly Distinct Interneurons , 2013, Nature Neuroscience.

[57]  P. Matthews,et al.  Polarity-Sensitive Modulation of Cortical Neurotransmitters by Transcranial Stimulation , 2009, The Journal of Neuroscience.

[58]  Lynne Kiorpes,et al.  Neural mechanisms underlying amblyopia , 1999, Current Opinion in Neurobiology.

[59]  B. Hangya,et al.  Central Cholinergic Neurons Are Rapidly Recruited by Reinforcement Feedback , 2015, Cell.

[60]  M. Stryker,et al.  A Cortical Circuit for Gain Control by Behavioral State , 2014, Cell.

[61]  Michael Bach,et al.  Long-Term Plasticity of Visually Evoked Potentials in Humans is Altered in Major Depression , 2007, Biological Psychiatry.

[62]  D. Stager,et al.  Binocular iPad treatment for amblyopia in preschool children. , 2014, Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus.

[63]  L. Maffei,et al.  The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex , 2008, Science.

[64]  H. Goltz,et al.  Effects of anisometropic amblyopia on visuomotor behavior, III: Temporal eye-hand coordination during reaching. , 2011, Investigative ophthalmology & visual science.

[65]  Michael P Stryker,et al.  Cortical Plasticity Induced by Inhibitory Neuron Transplantation , 2010, Science.

[66]  M. Stryker,et al.  Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons , 2014, Proceedings of the National Academy of Sciences.

[67]  T. M. Esdaille,et al.  Dark Light, Rod Saturation, and the Absolute and Incremental Sensitivity of Mouse Cone Vision , 2010, The Journal of Neuroscience.

[68]  R. Douglas,et al.  Behavioral assessment of visual acuity in mice and rats , 2000, Vision Research.

[69]  L. P. O'Keefe,et al.  Neuronal Correlates of Amblyopia in the Visual Cortex of Macaque Monkeys with Experimental Strabismus and Anisometropia , 1998, The Journal of Neuroscience.

[70]  Alexander J. Lingley,et al.  Susceptibility to monocular deprivation following immersion in darkness either late into or beyond the critical period , 2016, The Journal of comparative neurology.

[71]  Michael P Stryker,et al.  A cortical disinhibitory circuit for enhancing adult plasticity , 2015, eLife.

[72]  Mark F. Bear,et al.  Obligatory Role of NR2A for Metaplasticity in Visual Cortex , 2007, Neuron.

[73]  D. Mitchell,et al.  Recovery of visual functions in amblyopic animals following brief exposure to total darkness , 2016, The Journal of physiology.

[74]  Nicoletta Berardi,et al.  Reducing Intracortical Inhibition in the Adult Visual Cortex Promotes Ocular Dominance Plasticity , 2010, The Journal of Neuroscience.

[75]  Mark F. Bear,et al.  The BCM theory of synapse modification at 30: interaction of theory with experiment , 2012, Nature Reviews Neuroscience.

[76]  A. Kirkwood,et al.  Neuregulin-Dependent Regulation of Fast-Spiking Interneuron Excitability Controls the Timing of the Critical Period , 2016, The Journal of Neuroscience.

[77]  S. Klein,et al.  Detection and discrimination of the direction of motion in central and peripheral vision of normal and amblyopic observers , 1984, Vision Research.

[78]  F. Duffy,et al.  Dark rearing prolongs physiological but not anatomical plasticity of the cat visual cortex , 1985, The Journal of comparative neurology.

[79]  J. Bolz,et al.  Embryonic interneurons from the medial, but not the caudal ganglionic eminence trigger ocular dominance plasticity in adult mice , 2016, Brain Structure and Function.

[80]  Dennis M. Levi,et al.  Perceptual learning as a potential treatment for amblyopia: A mini-review , 2009, Vision Research.

[81]  R F Hess,et al.  Preliminary results of a physiologically based treatment of amblyopia. , 1978, The British journal of ophthalmology.

[82]  Takao K. Hensch,et al.  Valproate reopens critical-period learning of absolute pitch , 2013, Front. Syst. Neurosci..

[83]  A. Kirkwood,et al.  A Refractory Period for Rejuvenating GABAergic Synaptic Transmission and Ocular Dominance Plasticity with Dark Exposure , 2010, The Journal of Neuroscience.

[84]  L. Kiorpes Visual Processing in Amblyopia: Animal Studies , 2006, Strabismus.

[85]  M. Moseley,et al.  Amblyopia and Real-World Visuomotor Tasks , 2011, Strabismus.

[86]  E. Quinlan,et al.  Visual Deprivation Reactivates Rapid Ocular Dominance Plasticity in Adult Visual Cortex , 2006, The Journal of Neuroscience.

[87]  E. Birch,et al.  Amblyopia and binocular vision , 2013, Progress in Retinal and Eye Research.

[88]  E. Birch,et al.  Binocular iPad Game vs Patching for Treatment of Amblyopia in Children: A Randomized Clinical Trial. , 2016, JAMA ophthalmology.

[89]  Johannes J. Letzkus,et al.  A disinhibitory microcircuit for associative fear learning in the auditory cortex , 2011, Nature.

[90]  Siegrid Löwel,et al.  Progressive maturation of silent synapses governs the duration of a critical period , 2015, Proceedings of the National Academy of Sciences.

[91]  D. Levi,et al.  Binocular contrast discrimination needs monocular multiplicative noise , 2013, Journal of vision.

[92]  W. Singer,et al.  Ocular dominance in extrastriate cortex of strabismic amblyopic cats , 2002, Vision Research.

[93]  Simon Grant,et al.  Prehension deficits in amblyopia. , 2007, Investigative ophthalmology & visual science.

[94]  Nobuko Mataga,et al.  Experience-Dependent Pruning of Dendritic Spines in Visual Cortex by Tissue Plasminogen Activator , 2004, Neuron.

[95]  Pico Caroni,et al.  Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning , 2013, Nature.

[96]  Yumiko Yoshimura,et al.  Silent synapses persist into adulthood in layer 2/3 pyramidal neurons of visual cortex in dark-reared mice. , 2013, Journal of neurophysiology.

[97]  Johannes Burge,et al.  Continuous psychophysics: Target-tracking to measure visual sensitivity. , 2015, Journal of vision.

[98]  S. Löwel,et al.  Brief dark exposure restored ocular dominance plasticity in aging mice and after a cortical stroke , 2014, Experimental Gerontology.

[99]  D. Mitchell,et al.  Darkness Alters Maturation of Visual Cortex and Promotes Fast Recovery from Monocular Deprivation , 2013, Current Biology.

[100]  E. Birch,et al.  Effect of a Binocular iPad Game vs Part-time Patching in Children Aged 5 to 12 Years With Amblyopia: A Randomized Clinical Trial. , 2016, JAMA ophthalmology.