Abstract
In retinitis pigmentosa – a degenerative disease which often leads to incurable blindness- the loss of photoreceptors deprives the retina from a continuous excitatory input, the so-called dark current. In rodent models of this disease this deprivation leads to oscillatory electrical activity in the remaining circuitry, which is reflected in the rhythmic spiking of retinal ganglion cells (RGCs). It remained unclear, however, if the rhythmic RGC activity is attributed to circuit alterations occurring during photoreceptor degeneration or if rhythmic activity is an intrinsic property of healthy retinal circuitry which is masked by the photoreceptor’s dark current. Here we tested these hypotheses by inducing and analysing oscillatory activity in adult healthy (C57/Bl6) and blind mouse retinas (rd10 and rd1). Rhythmic RGC activity in healthy retinas was detected upon partial photoreceptor bleaching using an extracellular high-density multi-transistor-array. The mean fundamental spiking frequency in bleached retinas was 4.3 Hz; close to the RGC rhythm detected in blind rd10 mouse retinas (6.5 Hz). Crosscorrelation analysis of neighbouring wild-type and rd10 RGCs (separation distance <200 µm) reveals synchrony among homologous RGC types and a constant phase shift (∼70 msec) among heterologous cell types (ON versus OFF). The rhythmic RGC spiking in these retinas is driven by a network of presynaptic neurons. The inhibition of glutamatergic ganglion cell input or the inhibition of gap junctional coupling abolished the rhythmic pattern. In rd10 and rd1 retinas the presynaptic network leads to local field potentials, whereas in bleached retinas additional pharmacological disinhibition is required to achieve detectable field potentials. Our results demonstrate that photoreceptor bleaching unmasks oscillatory activity in healthy retinas which shares many features with the functional phenotype detected in rd10 retinas. The quantitative physiological differences advance the understanding of the degeneration process and may guide future rescue strategies.
Highlights
A major excitatory current in the retina is continuously generated by photoreceptors in the dark
The spike triggered average (STA) reveal the extracellular signal underneath the retinal ganglion cells (RGCs) soma and the propagating action potential along the unmyelinated axon (Fig. 1A) [18,19]
RGC spiking in constantly illuminated C57/Bl6 retinas is similar to spiking in rd10 retinas
Summary
A major excitatory current in the retina is continuously generated by photoreceptors in the dark This so-called darkcurrent increases in the developing retina, maintains a constant level throughout adulthood [1] and eventually disappears in the degenerative disease of retinitis pigmentosa, where mutations of the PDE6b [2] gene leads to rod degeneration and to incurable blindness. The origin of the rhythmic ganglion cell spiking in rd retinas – a mouse model of retinitis pigmentosa [2] - was assigned to presynaptic input [5,6,7,8] It may originate in the electrically coupled ON cone bipolar –amacrine cell network [10] or the AII amacrine cell alone [11] and effect the OFF pathway through chemical synapses [9]
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