Functional Stability of Retinal Ganglion Cells after Degeneration-Induced Changes in Synaptic Input

Abstract

Glutamate released from photoreceptors controls the activity and output of parallel pathways in the retina. When photoreceptors die because of degenerative diseases, surviving retinal networks are left without their major source of input, but little is known about how photoreceptor loss affects ongoing synaptic activity and retinal output. Here, we use patch-clamp recording and two-photon microscopy to investigate morphological and physiological properties of identified types of ON and OFF retinal ganglion cells (RGCs) in the adult (36 -210 d old) retinal degeneration rd-1/rd-1 mouse. We find that strong rhythmic synaptic input drives ongoing oscillatory spike activity in both ON and OFF RGCs at a fundamental "beating" frequency of ϳ10 Hz. Despite this aberrant activity, ON and OFF cells maintain their characteristic dendritic stratification, intrinsic firing properties, including rebound firing in OFF cells, balance of synaptic excitation and inhibition, and dendritic calcium signaling. Thus, RGCs are inherently stable during degeneration-induced retinal activity.

An Intrinsic Neural Oscillator in the Degenerating Mouse Retina

“…By P30 -P40, the one or two rows of photoreceptor cell bodies that remain (Carter-Dawson et al, 1978;Lin et al, 2009) do not appear to maintain their sensitivity to light (Strettoi et al, 2002), although they remain functionally connected with bipolar cells (Busskamp et al, 2010). In response to this sensory deafferentation, a marked increase in the spontaneous firing rates of ganglion cells has been observed previously (Ye and Goo, 2007;Margolis et al, 2008;Stasheff, 2008). To determine whether such activity arises in specific retinal circuits, we first recorded spike activity from single ganglion cells (P30 -P70) and subsequently characterized their morphologies.…”

“…The dendrites of ON and OFF ganglion cells stratify in the proximal (0 -60%) and distal (60 -100%) layers of the IPL, respectively, whereas those of ON-OFF cells stratify in both layers. Post hoc morphological analysis revealed that the dendritic stratification patterns of rd1 ganglion cells were maintained at a stage when photoreceptors are almost completely lost (Margolis et al, 2008;Mazzoni et al, 2008), allowing for their classification using similar criteria as that for wt ganglion cells. Examples of Neurobiotin-filled ON, OFF, or ON-OFF ganglion cells in the rd1 retina are illustrated in Figure 1 A (top).…”

“…Studies in the rd1 mouse model for RD demonstrate that the loss of photoreceptors is accompanied by a marked increase in spontaneous spike activity in output in ganglion cells (Ye and Goo, 2007;Margolis et al, 2008;Stasheff, 2008). Such retinal activity may underlie stimulus-independent visual photopsias, commonly experienced by patients with RD (for review, see Margolis and Detwiler, 2010).…”

“…A recent study by Margolis et al (2008) demonstrated that increased levels of excitatory and inhibitory synaptic inputs underlie hyperactivity in rd1 ganglion cells. However, the source and cellular mechanisms driving the presynaptic circuitry remain unclear.…”

“…Isolated bipolar cells have also been shown to exhibit a sustained 5-10 Hz membrane oscillation when depolarized, which is mediated by L-type voltage-gated Ca 2ϩ channels and Ca 2ϩ -dependent K ϩ channels (Burrone and Lagnado, 1997). Because these resonance frequencies are similar to those of ganglion cell activity (Margolis et al, 2008;Stasheff, 2008), it suggests that such mechanisms could drive activity during RD. Alternately, excitation could be driven indirectly through intrinsically active inhibitory amacrine cells.…”