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T. Vaithianathan, B. T. Sagdullaev; Functional Remodeling of Inner Retinal Synaptic Transmission During Photoreceptor Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2483.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal degenerative diseases (RDs) are mainly considered as photoreceptor dysfunction with the neural retina remaining relatively intact even after photoreceptor loss. This paradigm is being challenged by recent findings that reveal a massive structural remodeling of the retina during and after photoreceptor death. The purpose of this study was to establish how the progressive loss of photoreceptor-driven activity affects the physiological properties of the surviving retinal network and its ability to transmit synaptically-evoked signals.
The inner retinal network was assessed by recording whole-cell currents from morphologically identified ganglion cells (GCs) in mouse retinal slices. Excitatory and inhibitory currents were measured at the reversal holding potentials. The contributions of individual synaptic components were further dissected with specific pharmacological agents. Efficacy of synaptic transmission was assessed by stimulating presynaptic cells with brief current pulses. Responses were compared at different ages across two mouse models - rd1 and rd10 - featuring different onset times and rates of RD.
As photoreceptor degeneration progresses, GC spontaneous events exhibited aberrant excitatory and inhibitory currents composed of both ‘normal’ and atypical ‘gigantic’ events. Rd1 mice exhibited peak gigantic spontaneous events at P35-P52. In rd10 mice the gigantic spontaneous events were observed at a later stage (P50-P65). Application of specific glutamate receptor blockers eliminated the bursting activity, suggesting a presynaptic mechanism for its generation. Furthermore, application of specific blockers of GABA and glycine receptors eliminated the occurrence of bursting excitatory events, suggesting functional remodeling of amacrine cell network and its contribution to aberrant activity. In either models of RD, the increased noise caused by resting hyperactivity obscured the synaptically evoked currents.
Our data indicate that the structural remodeling during RD is paralleled by emergence of aberrant retinal signaling that compromise the transmission of synaptically evoked signals by reducing the signal-to-noise ratio. Importantly, these changes may occur regardless of the timing of RD onset and its interference with development (early in rd1 vs. late in rd10), the rate of its progression (fast in rd1 vs. slow in rd10), as well as the animals’ genetic background (C3H/HeJ of rd1 and C57Bl/6J of rd10).
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