title: Pharmacology of myopia and potential role for intrinsic retinal circadian rhythms.
abstract: Despite the high prevalence and public health impact of refractive errors, the mechanisms responsible for ametropias are poorly understood. Much evidence now supports the concept that the retina is central to the mechanism(s) regulating emmetropization and underlying refractive errors. Using a variety of pharmacologic methods and well-defined experimental eye growth models in laboratory animals, many retinal neurotransmitters and neuromodulators have been implicated in this process. Nonetheless, an accepted framework for understanding the molecular and/or cellular pathways that govern postnatal eye development is lacking. Here, we review two extensively studied signaling pathways whose general roles in refractive development are supported by both experimental and clinical data: acetylcholine signaling through muscarinic and/or nicotinic acetylcholine receptors and retinal dopamine pharmacology. The muscarinic acetylcholine receptor antagonist atropine was first studied as an anti-myopia drug some two centuries ago, and much subsequent work has continued to connect muscarinic receptors to eye growth regulation. Recent research implicates a potential role of nicotinic acetylcholine receptors; and the refractive effects in population surveys of passive exposure to cigarette smoke, of which nicotine is a constituent, support clinical relevance. Reviewed here, many puzzling results inhibit formulating a mechanistic framework that explains acetylcholine's role in refractive development. How cholinergic receptor mechanisms might be used to develop acceptable approaches to normalize refractive development remains a challenge. Retinal dopamine signaling not only has a putative role in refractive development, its upregulation by light comprises an important component of the retinal clock network and contributes to the regulation of retinal circadian physiology. During postnatal development, the ocular dimensions undergo circadian and/or diurnal fluctuations in magnitude; these rhythms shift in eyes developing experimental ametropia. Long-standing clinical ideas about myopia in particular have postulated a role for ambient lighting, although molecular or cellular mechanisms for these speculations have remained obscure. Experimental myopia induced by the wearing of a concave spectacle lens alters the retinal expression of a significant proportion of intrinsic circadian clock genes, as well as genes encoding a melatonin receptor and the photopigment melanopsin. Together this evidence suggests a hypothesis that the retinal clock and intrinsic retinal circadian rhythms may be fundamental to the mechanism(s) regulating refractive development, and that disruptions in circadian signals may produce refractive errors. Here we review the potential role of biological rhythms in refractive development. While much future research is needed, this hypothesis could unify many of the disparate clinical and laboratory observations addressing the pathogenesis of refractive errors.
authors: Department of Ophthalmology, University of Pennsylvania School of Medicine, Scheie Eye Institute, D-603 Richards Building, Philadelphia, PA 19104-6075, USA. stone@mail.med.upenn.edu
authors: Richard A
authors: RA
authors: Stone
authors: Machelle T
authors: MT
authors: Pardue
authors: P Michael
authors: PM
authors: Iuvone
authors: Tejvir S
authors: TS
authors: Khurana
mesh_terms: D000818:Animals; D057906:Circadian Clocks / Q000235:genetics; D002940:Circadian Rhythm / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D008027:Light; D009216:Myopia / Q000378:metabolism* / Q000503:physiopathology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012160:Retina / Q000502:physiology*
chemical_list: D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D004298:Dopamine
keywords: acetylcholine; ametropia; circadian rhythms; clock genes; dopamine; emmetropia; myopia; retina