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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    823—Striate Cortex: Ocular Dominance Plasticity

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    823.02: Nogo receptor 1 regulates plasticity of distinct circuits for binocularity and acuity

    Location: Halls B-H

    ">*C.-E. STEPHANY1, L. L. H. CHAN2, H. M. DORTON1, S. N. PARIVASH1, A. W. MCGEE1;
    1Saban Res. Institute, Children's Hosp. Los Angeles, Los Angeles, CA; 2Dept. of Electronic Engin., City Univ. of Hong Kong, Hong Kong, China

    Abstract Body: The closure of developmental sensitive or ‘critical’ periods consolidates neural circuitry refined by experience but also limits plasticity that could compensate for maladaptive alterations in brain function induced earlier in life. For example, discordant vision during childhood induces amblyopia, a visual disorder affecting an estimated 3% of the U.S. population that comprises several deficits in spatial vision including lower visual acuity. The genes and mechanisms that direct the transition from plasticity to consolidation of brain circuitry remain poorly understood.
    In animal models of amblyopia, monocular deprivation (MD) by suturing closed one eye throughout the critical period both shifts ocular dominance and impedes the maturation of acuity by the deprived eye. Analogous to clinical findings, acuity deficits persist if normal vision is restored after the critical period. The nogo-66 receptor (NgR1) is required to close the critical period for developmental plasticity of eye dominance. Here we report that NgR1 mutant mice exhibit spontaneous improvement of visual acuity after prolonged abnormal visual experience. Interestingly, selective deletion of NgR1 in parvalbumin-positive (PV) interneurons maintains developmental ocular dominance plasticity in adults but does not rescue deficits in acuity. Thus, PV neurons govern closure of the critical period, but mechanisms of plasticity for binocularity are not sufficient for recovery from amblyopia.

    Lay Language Summary: Our research identifies a gene that impedes recovery from amblyopia (also known as lazy eye). Removing this gene restores flexibility to the circuitry of the visual system and improves acuity in adult mice. In amblyopia, the connections between the brain and the dominant eye are magnified at the expense of the affected eye; this exaggerated eye dominance is associated with poor vision. Interestingly, our research also reveals that restoring normal eye dominance is not enough to improve vision.
    Poorly coordinated vision caused by misalignment of the two eyes or differences in the depth of focus induces amblyopia in children. This prevalent visual disorder results in lower visual acuity in the non-dominant eye. Patching the dominant eye is an effective treatment in younger children because they are still within the developmental ‘critical period’ and the circuitry of the visual system is flexible. During the critical period, altering visual experience by patching can modify the connections between the eyes and brain to normalize eye dominance and improve vision through the affected eye. However, after the critical period, these connections are less plastic, and beyond adolescence, patients with amblyopia are largely resistant to this therapeutic intervention. Our study reveals that the nogo receptor 1 (NgR1) gene limits improvement of vision in adults with amblyopia. Blocking the function of this gene may represent a potential therapeutic approach to improve vision in adults with amblyopia.
    In our research, we use mice as a model system for amblyopia because they have a similar developmental trajectory to humans and also confer essential genetic advantages. Mice lacking NgR1 retain plasticity of eye dominance in adulthood. However, previous studies have not addressed whether or not this plasticity is sufficient to drive functional recovery of the poor vision associated with amblyopia. Here, we tested this hypothesis by measuring visual acuity in adult amblyopic mutant mice. To induce amblyopia, we perturbed vision by temporarily closing one eye during the critical period akin to the period of discordant vision in childhood that causes this disorder. To evaluate visual acuity, we employed a behavioral task in which mice swam toward a target displaying a visual stimulus. When the stimulus was made smaller, much like the smaller letters on an eye chart, mice were unable to recognize the target and failed the task. We found that mice lacking the NgR1 gene have significantly better visual acuity than normal amblyopic mice.
    Next, we explored the relationship between eye dominance and visual acuity. Abnormal vision during the critical period adversely affects both, but how are they related? Circuits in the brain are largely composed of two types of connections—those that excite other neurons to fire and those that inhibit other neurons from firing. We used advanced genetics to delete the NgR1 gene only from the inhibitory circuits. Interestingly, we find that this is sufficient to retain plasticity of eye dominance in adulthood, but doesn’t improve vision in mice with
    amblyopia. Therefore, NgR1 regulates the plasticity of separate circuits within the visual system that mediate eye dominance and visual acuity.