In the CNS, neuronal cell death triggers a compensatory response within surviving tissue (Schnitzler and Gross, 2005
). In the visual system, retinal degeneration (RD) results in photoreceptor cell death, which is followed by structural remodeling of surviving retinal tissue (Marc et al., 2003
), including changes in synaptic connectivity (Strettoi et al., 2004
) and receptor expression (Peng et al., 2000
; Chua et al., 2009
), leading to aberrant oscillatory activity (Margolis et al., 2008
; Stasheff, 2008
). Though significant progress has been made in characterizing these changes and identifying the source of this activity, it remains unclear (i) how different retinal pathways are affected by remodeling, (ii) what mechanism initiates this oscillatory activity, and (iii) what functional implications this noise has on the surviving retinal circuitry.
Multiple retinal pathways encode different aspects of the sensory signal. At the level of retinal output, this segregation is reflected by numerous types of retinal ganglion cells (GCs; Wassle, 2004
). Unlike other retinal cells, GCs remain structurally (Mazzoni et al., 2008
) and functionally (Margolis et al., 2008
) stable during RD, which allows the physiological effects of structural remodeling in presynaptic cells to be observed by monitoring GC activity. Given the diversity of GCs, previous physiological characterizations of RD GCs, which considered only three cell classes (Margolis et al., 2008
; Borowska et al., 2011
), may not fully describe pathway-specific differences in retinal remodeling. We took physiological recordings from a large population of GCs from rd1
mouse retinas, which were classified into 11 groups based on morphological measurements. The occurrence and properties of aberrant oscillations varied largely with cell class, suggesting differences between visual pathways in their susceptibility to RD-induced functional changes.
Various cell types are known to produce oscillations in healthy retina. However, the cells responsible for oscillations in RD retina remain unclear. The source of the aberrant activity has been attributed to dystrophic bipolar cells (BCs; Menzler and Zeck, 2011
) or, in contrast, to a circuit of dystrophic AII amacrine and cone BCs (Borowska et al., 2011
). We combined single-cell recordings with pharmacological analysis to show that an amacrine cell (AC) oscillator is necessary and sufficient to drive aberrant activity in rd1
retina. BC oscillations are present in both wt
retina, but are unaffected by RD and are unnecessary for aberrant activity in rd1
Sensory loss due to photoreceptor death due to photoreceptor death has been well characterized (Strettoi et al., 2002
; Gargini et al., 2007
; Stasheff, 2008
; Stasheff et al., 2011
), but the functional impact of aberrant activity within surviving retinal tissue has not. By stimulating the inner retina with electrical pulses, we demonstrate that the efficiency of signal transmission is greatly reduced by synaptic noise, which increases as degeneration progresses.
Together, these data provide potential targets for treatment of RD, demonstrating variability in pathway-specific resilience to remodeling, identifying an independent source of aberrant oscillations in retina, and showing that eliminating oscillatory noise could be a treatment in itself.