Binocular visual training to promote recovery from monocular deprivation.

Abnormal early visual experience often leads to poor vision, a condition called amblyopia. Two recent approaches to treating amblyopia include binocular therapies and intensive visual training. These reflect the emerging view that amblyopia is a binocular deficit caused by increased neural noise and poor signal-in-noise integration. Most perceptual learning studies have used monocular training; however, a recent study has shown that binocular training is effective for improving acuity in adult human amblyopes. We used an animal model of amblyopia, based on monocular deprivation, to compare the effect of binocular training either during or after the critical period for ocular dominance plasticity (early binocular training vs. late binocular training). We used a high-contrast, orientation-in-noise stimulus to drive the visual cortex because neurophysiological findings suggest that binocular training may allow the nondeprived eye to teach the deprived eye's circuits to function. We found that both early and late binocular training promoted good visual recovery. Surprisingly, we found that monocular deprivation caused a permanent deficit in the vision of both eyes, which became evident only as a sleeper effect following many weeks of visual training.

Experience-dependent central vision deficits: Neurobiology and visual acuity.

Abnormal visual experience during childhood often leads to amblyopia, with strong links to binocular dysfunction that can include poor acuity in both eyes, especially in central vision. In animal models of amblyopia, the non-deprived eye is often considered normal and what limits binocular acuity. This leaves open the question whether monocular deprivation (MD) induces binocular dysfunction similar to what is found in amblyopia. In previous studies of MD cats, we found a loss of excitatory receptors restricted to the central visual field representation in visual cortex (V1), including both eyes' columns. This led us to ask two questions about the effects of MD: how quickly are receptors lost in V1? and is there an impact on binocular acuity? We found that just a few hours of MD caused a rapid loss of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor proteins across all of V1. But after a few days of MD, there was recovery in the visual periphery, leaving a loss of AMPA receptors only in the central region of V1. We reared animals with early MD followed by a long period of binocular vision and found binocular acuity deficits that were greatest in the central visual field. Our results suggest that the greater binocular acuity deficits in the central visual field are driven in part by the long-term loss of AMPA receptors in the central region of V1.

Effects of Fluoxetine and Visual Experience on Glutamatergic and GABAergic Synaptic Proteins in Adult Rat Visual Cortex.

Fluoxetine has emerged as a novel treatment for persistent amblyopia because in adult animals it reinstates critical period-like ocular dominance plasticity and promotes recovery of visual acuity. Translation of these results from animal models to the clinic, however, has been challenging because of the lack of understanding of how this selective serotonin reuptake inhibitor affects glutamatergic and GABAergic synaptic mechanisms that are essential for experience-dependent plasticity. An appealing hypothesis is that fluoxetine recreates a critical period (CP)-like state by shifting synaptic mechanisms to be more juvenile. To test this we studied the effect of fluoxetine treatment in adult rats, alone or in combination with visual deprivation [monocular deprivation (MD)], on a set of highly conserved presynaptic and postsynaptic proteins (synapsin, synaptophysin, VGLUT1, VGAT, PSD-95, gephyrin, GluN1, GluA2, GluN2B, GluN2A, GABAAα1, GABAAα3). We did not find evidence that fluoxetine shifted the protein amounts or balances to a CP-like state. Instead, it drove the balances in favor of the more mature subunits (GluN2A, GABAAα1). In addition, when fluoxetine was paired with MD it created a neuroprotective-like environment by normalizing the glutamatergic gain found in adult MDs. Together, our results suggest that fluoxetine treatment creates a novel synaptic environment dominated by GluN2A- and GABAAα1-dependent plasticity.

Experience-dependent changes in excitatory and inhibitory receptor subunit expression in visual cortex.

Experience-dependent development of visual cortex depends on the balance between excitatory and inhibitory activity. This activity is regulated by key excitatory (NMDA, AMPA) and inhibitory (GABA(A)) receptors. The composition of these receptors changes developmentally, affecting the excitatory-inhibitory (E/I) balance and synaptic plasticity. Until now, it has been unclear how abnormal visual experience affects this balance. To examine this question, we measured developmental changes in excitatory and inhibitory receptor subunits in visual cortex following normal visual experience and monocular deprivation. We used Western blot analysis to quantify expression of excitatory (NR1, NR2A, NR2B, GluR2) and inhibitory (GABA(A)α1, GABA(A)α3) receptor subunits. Monocular deprivation promoted a complex pattern of changes in receptor subunit expression that varied with age and was most severe in the region of visual cortex representing the central visual field. To characterize the multidimensional pattern of experience-dependent change in these synaptic mechanisms, we applied a neuroinformatics approach using principal component analysis. We found that monocular deprivation (i) causes a large portion of the normal developmental trajectory to be bypassed, (ii) shifts the E/I balance in favor of more inhibition, and (iii) accelerates the maturation of receptor subunits. Taken together, these results show that monocularly deprived animals have an abnormal balance of the synaptic machinery needed for functional maturation of cortical circuits and for developmental plasticity. This raises the possibility that interventions intended to treat amblyopia may need to address multiple synaptic mechanisms to produce optimal recovery.

Development of human visual cortex: a balance between excitatory and inhibitory plasticity mechanisms.

Formation of neural circuitry in the developing visual cortex is shaped by experience during the critical period. A number of mechanisms, including N-methyl-D-aspartate (NMDA) receptor activation and gamma-aminobutyric acid (GABA)-mediated inhibition, are crucial in determining onset and closure of the critical period for visual plasticity. Animal models have shown that a threshold level of tonic inhibition must be reached for critical period plasticity to occur and that NMDA receptors contribute to Hebbian synaptic plasticity in the developing visual cortex. There are a number of developmental changes in these glutamatergic and GABAergic mechanisms that have been linked to plasticity; however, those changes have been shown only in animal models, and their development in the human visual cortex is not known. We have addressed this question by studying the expression of the major glutamatergic receptors, GABA(A) receptors, and glutamic acid decarboxylase (GAD) isoforms during the first 6 years of postnatal development of human visual cortex. There are significant changes in the expression of these proteins during postnatal development of human visual cortex. The time course of the changes is quite prolonged and suggests that it may set the pace for the prolonged critical period in human visual development. The changes also affect the nature of spatial and temporal integration in visual cortical neurons and thereby contribute to the maturation of visual functions.