Emergence of Sustained Spontaneous Hyperactivity and Temporary Preservation of off Responses in Ganglion Cells of the Retinal Degeneration (rd1) Mouse

Abstract

Stasheff SF. Emergence of sustained spontaneous hyperactivity and temporary preservation of OFF responses in ganglion cells of the retinal degeneration (rd1) mouse. J Neurophysiol 99: 1408 -1421, 2008. First published January 23, 2008 doi:10.1152/jn.00144.2007. Complex alterations in the anatomy of outer retinal pathways accompany photoreceptor degeneration in the rd1 mouse model of retinitis pigmentosa, whereas inner retinal neurons appear relatively preserved. However, the progressive loss of photoreceptor input likely alters the neural circuitry of the inner retina. This study investigated resulting changes in the activity of surviving ganglion cells. Multielectrode recording monitored spontaneous and light-evoked extracellular action potentials simultaneously from 30 to 90 retinal ganglion cells of wild-type (wt) or rd1 mice. In rd1 mice, this activity evolves through three phases. First, normal spontaneous "waves" of correlated firing are seen at postnatal day 7 (P7) and last until shortly after eye opening. Second, at P14, full-field light flashes evoke reliable responses in many cells, with preferential preservation of OFF responses. These diminish as photoreceptor degeneration progresses. Third, once light-evoked responses have disappeared in early adulthood, surviving rd1 ganglion cells fire at a much higher spontaneous frequency than normal, sometimes in rhythmic bursts that are distinct from the developmental "waves." This hyperactivity is sustained well into adulthood, for weeks after photoreceptors have disappeared. Thus striking alterations occur in inner retinal physiology as retinal degeneration progresses in the rd1 mouse. Blindness occurs in the face of sustained hyperactivity among ganglion cells, which remain viable for months despite this activity. ON and OFF responses are differentially affected in early stages of degeneration. While the source of these changes remains to be learned, such features should be considered in designing more effective treatments for these disorders.

An Intrinsic Neural Oscillator in the Degenerating Mouse Retina

“…The average firing rate was 5.5 Ϯ 1.4 Hz for ON cells (n ϭ 20), 10.6 Ϯ 1.9 Hz for OFF cells (n ϭ 25), and 7.1 Ϯ 2.0 Hz for ON-OFF cells (n ϭ 13), with no statistical significant difference between the three groups ( p ϭ 0.12, Kruskal-Wallis test). Such variability in ganglion cell activity is consistent with previous reports (Stasheff, 2008: median spike rate was 3-8 Hz; range, 0 -40 Hz for all types of cells in the ganglion cell layer; P28 -P51) and suggest that circuits can exist in different states.…”

“…Spectral analysis of spike activity in these cells revealed a clear peak in the power corresponding to the fundamental frequency of the oscillatory response (12.6 Ϯ 1.7 Hz; n ϭ 19) (16 Hz/ 0.060 ms in the example illustrated in Fig. 1Cii,Ciii), consistent with previous reports (Ye and Goo, 2007;Margolis et al, 2008;Stasheff, 2008). Such oscillatory components were observed in approximately one-third of all three classes of ganglion cells (OFF, 36%; ON, 30%; ON-OFF, 31%).…”

“…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.…”

“…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).…”

“…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.…”