Impairment of the transient pupillary light reflex in Rpe65(-/-) mice and humans with leber congenital amaurosis.

PURPOSE To determine the impairment of the transient pupillary light reflex (TPLR) due to severe retinal dysfunction and degeneration in a murine model of Leber congenital amaurosis (LCA) and in patients with the disease. METHODS Direct TPLR was elicited in anesthetized, dark-adapted Rpe65(-/-) and control mice with full-field light stimuli (0.1 second duration) of increasing intensities (-6.6 to +2.3 log scot-cd. m(-2)). 9-cis-Retinal was administered orally to a subset of Rpe65(-/-) mice, and TPLR was recorded 48 hours after the treatment. TPLR was also measured in a group of patients with LCA. RESULTS Baseline pupillary diameters in Rpe65(-/-) and control mice were similar. TPLR thresholds of Rpe65(-/-) mice were elevated by 5 log units compared with those of control animals. The waveform of the TPLR in Rpe65(-/-) mice was similar to that evoked by 4.8-log-unit dimmer stimuli in control mice. Treatment of Rpe65(-/-) mice with 9-cis-retinal lowered the TPLR threshold by 2.1 log units. Patients with LCA had baseline pupillary diameters similar to normal, but the TPLR was abnormal, with thresholds elevated by 3 to more than 6 log units. When adjusted to the elevation of TPLR threshold, pupillary constriction kinetics in most patients were similar to those in normal subjects. CONCLUSIONS Pupillometry was used to quantify visual impairment and to probe transmission of retinal signals to higher nervous centers in a murine model of LCA and in patients with LCA. Mouse results were consistent with a dominant role of image-forming photoreceptors driving the early phase of the TPLR when elicited by short-duration stimuli. The objective and noninvasive nature of the TPLR measurement, and the observed post-treatment change toward normal in the animal model supports the notion that this may be a useful outcome measure in future therapeutic trials of LCA.

[1]  J. Lisman,et al.  Support for the equivalent light hypothesis for RP , 1995, Nature Medicine.

[2]  M. Banks,et al.  Pupillometric measurement of difference spectra for three color receptors in an adult and a four-year-old. , 1974, Vision research.

[3]  Jean Bennett,et al.  Gene therapy restores vision in a canine model of childhood blindness , 2001, Nature Genetics.

[4]  H. S. Thompson,et al.  Pupillary defects in retinitis pigmentosa. , 1985, American journal of ophthalmology.

[5]  J. Hetling,et al.  Sensitivity and kinetics of mouse rod flash responses determined in vivo from paired‐flash electroretinograms , 1999, The Journal of physiology.

[6]  D. Birch,et al.  Pupil size following dark adaptation in patients with retinitis pigmentosa. , 2001, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[7]  E. Gaillard,et al.  The optical properties of the anterior segment of the eye: implications for cortical cataract. , 1999, Experimental eye research.

[8]  Longtin,et al.  Noise and critical behavior of the pupil light reflex at oscillation onset. , 1990, Physical review. A, Atomic, molecular, and optical physics.

[9]  Robert J. Lucas,et al.  Calcium Imaging Reveals a Network of Intrinsically Light-Sensitive Inner-Retinal Neurons , 2003, Current Biology.

[10]  T Michael Redmond,et al.  Acute radiolabeling of retinoids in eye tissues of normal and rpe65-deficient mice. , 2003, Investigative ophthalmology & visual science.

[11]  C. Bradshaw,et al.  Comparison of the effects of venlafaxine, paroxetine and desipramine on the pupillary light reflex in man , 1999, Psychopharmacology.

[12]  F. Campbell,et al.  The spectral sensitivity of the consensual light reflex , 1962, The Journal of physiology.

[13]  D. Jewett,et al.  Autonomic components of the human pupillary light reflex. , 1990, Investigative ophthalmology & visual science.

[14]  D L Mayer,et al.  Vision in Leber congenital amaurosis. , 1996, Archives of ophthalmology.

[15]  E. Pugh,et al.  Extreme responsiveness of the pupil of the dark-adapted mouse to steady retinal illumination. , 1998, Investigative ophthalmology & visual science.

[16]  A. D. den Hollander,et al.  Molecular genetics of Leber congenital amaurosis. , 2002, Human molecular genetics.

[17]  Randy H Kardon,et al.  Pupil light reflex in normal and diseased eyes: diagnosis of visual dysfunction using waveform partitioning. , 2003, Ophthalmology.

[18]  C. Grimm,et al.  New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis , 2001, Nature Genetics.

[19]  D. Copenhagen,et al.  Visual Stimulation Is Required for Refinement of ON and OFF Pathways in Postnatal Retina , 2003, Neuron.

[20]  C. M. Cicerone,et al.  Retinal sensitivity measured by the pupillary light reflex in RCS and albino rats , 1982, Vision Research.

[21]  E. Fazzi,et al.  Leber's congenital amaurosis: an update. , 2003, European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society.

[22]  E. Pugh,et al.  The Origin of the Major Rod- and Cone-Driven Components of the Rodent Electroretinogram and the Effect of Age and Light-Rearing History on the Magnitude of These Components , 1998 .

[23]  K. Palczewski,et al.  A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  L. P. Morin,et al.  Retinal ganglion cell projections to the hamster suprachiasmatic nucleus, intergeniculate leaflet, and visual midbrain: Bifurcation and melanopsin immunoreactivity , 2003, The Journal of comparative neurology.

[25]  R. Lund,et al.  Changes in the pupillary light reflex of pigmented royal college of surgeons rats with Age. , 1998, Experimental eye research.

[26]  R. Foster.  Keeping an eye on the time: the Cogan Lecture. , 2002, Investigative ophthalmology & visual science.

[27]  J. Robson,et al.  The Scotopic Threshold Response of the Dark‐Adapted Electroretinogram of the Mouse , 2002, The Journal of physiology.

[28]  H. Ikeda,et al.  Luminance and darkness detectors in the olivary and posterior pretectal nuclei and their relationship to the pupillary light reflex in the rat , 2004, Experimental Brain Research.

[29]  J. Beckham,et al.  Keeping an eye on time. , 1993, The Healthcare Forum journal.

[30]  K. Yau,et al.  Diminished Pupillary Light Reflex at High Irradiances in Melanopsin-Knockout Mice , 2003, Science.

[31]  M. Naash,et al.  Rod phototransduction in transgenic mice expressing a mutant opsin gene. , 1996, Journal of the Optical Society of America. A, Optics, image science, and vision.

[32]  T. Williams,et al.  Photostasis and Related Phenomena , 1998, Springer US.

[33]  D. Berson,et al.  Strange vision: ganglion cells as circadian photoreceptors , 2003, Trends in Neurosciences.

[34]  S. Peirson,et al.  Melanopsin retinal ganglion cells and the maintenance of circadian and pupillary responses to light in aged rodless/coneless (rd/rd cl) mice , 2003, The European journal of neuroscience.

[35]  T. Aleman,et al.  Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[36]  M. A. Bouman,et al.  Differential threshold measurements on the light reflex of the human pupil. , 1958, A.M.A. archives of ophthalmology.

[37]  R. Lund,et al.  The pupillary light response: Assessment of function mediated by intracranial retinal transplants , 1995, Neuroscience.

[38]  I. E. Loewenfeld,et al.  The Pupil: Anatomy, Physiology, and Clinical Applications , 1999 .

[39]  M. Kondo,et al.  Multifocal pupillary light response fields in normal subjects and patients with visual field defects , 2001, Vision Research.

[40]  M. Alpern,et al.  Adaptation of the pupil light reflex. , 1972, Vision research.

[41]  G. Fain,et al.  Spontaneous activity of opsin apoprotein is a cause of Leber congenital amaurosis , 2003, Nature Genetics.

[42]  D. Bok,et al.  Rpe65 is necessary for production of 11-cis-vitamin A in the retinal visual cycle , 1998, Nature Genetics.

[43]  E N Pugh,et al.  Analysis of ERG a-wave amplification and kinetics in terms of the G-protein cascade of phototransduction. , 1994, Investigative ophthalmology & visual science.

[44]  L. Pinto,et al.  Visually evoked eye movements in the mouse (Mus musculus) , 1976, Vision Research.

[45]  D. Berson,et al.  Phototransduction by Retinal Ganglion Cells That Set the Circadian Clock , 2002, Science.

[46]  K. Yau,et al.  Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity , 2002, Science.

[47]  G. H. Jacobs,et al.  Retinal receptors in rodents maximally sensitive to ultraviolet light , 1991, Nature.

[48]  Jian-xing Ma,et al.  Isorhodopsin rather than rhodopsin mediates rod function in RPE65 knock-out mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Pilar Herreros de Tejada,et al.  Behavioral estimates of absolute visual threshold in mice , 1997, Vision Research.

[50]  E. Birch,et al.  Pupillometric measures of retinal sensitivity in infants and adults with retinitis pigmentosa , 1987, Vision Research.

[51]  Robert J. Lucas,et al.  Characterization of an ocular photopigment capable of driving pupillary constriction in mice , 2001, Nature Neuroscience.

[52]  C. Ellis,et al.  The pupillary light reflex in normal subjects. , 1981, The British journal of ophthalmology.

[53]  Edwin M Stone,et al.  Clinicopathologic effects of mutant GUCY2D in Leber congenital amaurosis. , 2003, Ophthalmology.

[54]  K. N. Ogle,et al.  COMPARISON OF VISUAL AND PUPILLARY LIGHT THRESHOLDS IN PERIPHERY. , 1964, Archives of ophthalmology.

[55]  L. Chalupa,et al.  The visual neurosciences , 2004 .

[56]  Randy H Kardon,et al.  Greater pupillary escape differentiates central from peripheral visual field loss. , 2002, Ophthalmology.

[57]  M. Biel,et al.  Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice , 2003, Nature.

[58]  A. J. Roman,et al.  Interocular asymmetry of visual function in heterozygotes of X-linked retinitis pigmentosa. , 1989, Experimental eye research.

[59]  R. Kardon,et al.  Automated pupil perimetry. Pupil field mapping in patients and normal subjects. , 1991, Ophthalmology.

[60]  P. Detwiler,et al.  Recovery of Visual Functions in a Mouse Model of Leber Congenital Amaurosis* , 2002, The Journal of Biological Chemistry.

[61]  Edwin M Stone,et al.  Crumbs homolog 1 (CRB1) mutations result in a thick human retina with abnormal lamination. , 2003, Human molecular genetics.

[62]  R. Lund,et al.  Development of Light‐activated Pupilloconstriction in Rats as Mediated by Normal and Transplanted Retinae , 1992, The European journal of neuroscience.

[63]  P C Jackson,et al.  Reduced activity during development delays the normal rearrangement of synapses in the rabbit ciliary ganglion. , 1983, The Journal of physiology.