Cellular origin of spontaneous ganglion cell spike activity in animal models of retinitis pigmentosa

Abstract

Here we review evidence that loss of photoreceptors due to degenerative retinal disease causes an increase in the rate of spontaneous ganglion spike discharge. Information about persistent spike activity is important since it is expected to add noise to the communication between the eye and the brain and thus impact the design and effective use of retinal prosthetics for restoring visual function in patients blinded by disease. Patch-clamp recordings from identified types of ON and OFF retinal ganglion cells in the adult (36-210 d old) rd1 mouse show that the ongoing oscillatory spike activity in both cell types is driven by strong rhythmic synaptic input from presynaptic neurons that is blocked by CNQX. The recurrent synaptic activity may arise in a negative feedback loop between a bipolar cell and an amacrine cell that exhibits resonant behavior and oscillations in membrane potential when the normal balance between excitation and inhibition is disrupted by the absence of photoreceptor input.

Figure 1

Spontaneous activity in rd1 alpha ganglion cell. (a) Whole-cell current clamp recordings of ongoing spiking activity in wild-type (top) and rd1 (bottom) ON-type retinal ganglion cells. Horizontal tick mark at left indicates −60 mV for wt and −70 mV for rd1 cells, respectively. (b) Whole-cell voltage clamp recording of ongoing synaptic currents in an rd1 ON ganglion cell before (left) and after (right) bath application of CNQX.

Figure 2

Retinal circuit that may give rise to spontaneous ganglion cell spike activity. The membrane potential of the amacrine cell oscillates spontaneously due to resonance (see text) which drives oscillatory release of inhibitory transmitter on to the bipolar cell causing oscillations in bipolar voltage triggering pulsatile release of excitatory transmitter on to the ganglion cell, causing rhythmic spike discharge, and the amacrine cell with negative feedback to the bipolar. The reverberating input to the ganglion cell arises from the presence of a negative feedback loop that includes a resonant oscillator.

Figure 3

Loose patch extracellular recording of spontaneous spike activity from wild-type (non-dystrophic) retinal ganglion cell perfused with Control Ames solution without (top traces (a) and (b)) and with (lower traces (a) and (b)) the addition of mixture of inhibitory synaptic blockers containing 40 uM Gabazine, 50 uM TPMPA, and 1 uM Strychnine. Boxed region outlined by the dash lines in (a) are shown on a faster time in (b). The trace shown on an expanded time scale in control Ames (b) was taken from a region of trace in (a) that was shifted to the right to avoid the period of baseline instability.