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J. T. Borowska, S. Trenholm, G. B. Awatramani; Intrinsic Mechanisms in Bipolar Cells Drive Spontaneous Network Activity During Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2486.
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The loss of photoreceptors during retinal degeneration (RD) leads to a paradoxical increase in spontaneous activity in remnant retinal networks. We sought to identify the source of this activity.
We applied patch-clamp, pharmacological and anatomical techniques to investigate the physiological properties of identified cell types in the retina of the rd1 mouse (P30-70), which lose most of their photoreceptors within a few weeks of eye-opening.
We observed high rates (10 + 8 Hz) of spontaneous action potentials in ganglion cells, which did not appear to be specific to ON/OFF pathways or to particular cell-types. Voltage-clamp analysis revealed that ganglion cells received robust spontaneous inhibitory (sIPSCs) and excitatory (sEPSCs) inputs, suggesting a presynaptic origin for hyperactivity. Pharmacological blockade of excitatory receptors largely abolished sIPSCs indicating that they were driven by excitatory pathways. In contrast, antagonizing inhibitory receptors unmasked large oscillatory bursting patterns of AMPA/NMDA mediated EPSCs in a majority of ganglion cells. Additional block of photoreceptor inputs using NBQX and APB did not significantly alter the frequency of events as reflected in the NMDA component of the EPSCs, indicating that activity did not arise in the outer retina. Consistent with this notion, direct voltage-clamp recordings from ON and OFF bipolar cells revealed sparse excitatory synaptic input into these cells. However, current-clamp recordings revealed low amplitude voltage-dependent spike-like events that persisted in the presence of a cocktail of synaptic blockers, thus providing direct evidence that these cells are intrinsically active.
Hyperactivity in remnant networks in the rd1 retina is not circuit specific and appears to arise from properties intrinsic to excitatory bipolar cells. Inhibitory circuits do not appear to play an obligatory role in the generation of spontaneous activity, but rather serve to gate excitatory flow, thereby preventing runaway excitation.
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