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. 2014 Jan 28;9(1):e86253.
doi: 10.1371/journal.pone.0086253. eCollection 2014.

Network oscillations drive correlated spiking of ON and OFF ganglion cells in the rd1 mouse model of retinal degeneration

David J Margolis  1 , Andrew J Gartland  2 , Joshua H Singer  3 , Peter B Detwiler  2
Affiliations

Network oscillations drive correlated spiking of ON and OFF ganglion cells in the rd1 mouse model of retinal degeneration

David J Margolis et al. PLoS One. .

Abstract

Following photoreceptor degeneration, ON and OFF retinal ganglion cells (RGCs) in the rd-1/rd-1 mouse receive rhythmic synaptic input that elicits bursts of action potentials at ∼ 10 Hz. To characterize the properties of this activity, RGCs were targeted for paired recording and morphological classification as either ON alpha, OFF alpha or non-alpha RGCs using two-photon imaging. Identified cell types exhibited rhythmic spike activity. Cross-correlation of spike trains recorded simultaneously from pairs of RGCs revealed that activity was correlated more strongly between alpha RGCs than between alpha and non-alpha cell pairs. Bursts of action potentials in alpha RGC pairs of the same type, i.e. two ON or two OFF cells, were in phase, while bursts in dissimilar alpha cell types, i.e. an ON and an OFF RGC, were 180 degrees out of phase. This result is consistent with RGC activity being driven by an input that provides correlated excitation to ON cells and inhibition to OFF cells. A2 amacrine cells were investigated as a candidate cellular mechanism and found to display 10 Hz oscillations in membrane voltage and current that persisted in the presence of antagonists of fast synaptic transmission and were eliminated by tetrodotoxin. Results support the conclusion that the rhythmic RGC activity originates in a presynaptic network of electrically coupled cells including A2s via a Na(+)-channel dependent mechanism. Network activity drives out of phase oscillations in ON and OFF cone bipolar cells, entraining similar frequency fluctuations in RGC spike activity over an area of retina that migrates with changes in the spatial locus of the cellular oscillator.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Cell targeting and spike train auto-correlograms.
A. Fluorescence images of retina in presence of bath applied sulforhodamine, a counterstain showing intact cell bodies (dark) on lighter fluorescent background with examples of a large (alpha) and small (non-alpha) somas RGCs indicated by asterisks. Two-photon Z-projection images of alpha (B) and non-alpha (C) RGCs following internal whole cell dialysis with pipette filling solution that contains 140 uM OGB-1. Scale bars 30 and 15 um, respectively. Spike train rasters recorded from alpha (D) and non-alpha (E) RGCs and corresponding auto-correlograms (black traces) based on 166 s records, 2 ms bin widths. Red traces are auto-correlograms using shuffled spike trains (see Methods & Materials). Insets show auto-correlograms on expanded time scales to illustrate reduced spike probability during a ∼5 to 10 ms refractory period following a spike.
Figure 2
Figure 2. Auto- and cross-correlograms of spike trains recorded from OFF/OFF (A) and OFF/ON (B) alpha RGCs pairs.
Rasterized spike trains recorded simultaneously from a pair of OFF alpha RGCs (A) and from an OFF and ON alpha RGC pair (B), showing in and out of phase spike generation, respectively. Row of four graphs below raster traces show auto-correlograms of spike trains recorded from the two cells in A (left) and B (right), total record lengths of 181 and 121 s, respectively. Bottom plots are cross-correlograms for the OFF/OFF (left) and OFF/ON (right) alpha RGC pairs. In all correlograms black and red traces plot auto- and cross-correlations of original and shuffled spike times, respectively. OFF alpha cells identified as sustained or transient subtypes labeled OFFS and OFFT, respectively.
Figure 3
Figure 3. Correlation analysis of spike trains recorded from an alpha and non-alpha RGCs.
A. Rasterized spike trains recorded simultaneously from a non-alpha (top trace) and OFF alpha RGC. B, C. Auto-correlograms of spontaneous spike activity in non-alpha and OFF alpha RGCs in A, respectively. Inserts show auto-correlation on expanded time scale. C. Cross-correlogram of spike trains recorded from RGCs in part A, total record lengths 287 s. In all panels black and red traces plot auto- and cross-correlations of original and shuffled spike times, respectively.
Figure 4
Figure 4. Phase stability in spike firing in paired recordings.
The phase relationship of spike generation in trains recorded simultaneously from pairs of like-type alpha RGCs, i.e. both ON cells (A) and both OFF cells (B) and from un-like type alpha RGCs, i.e. an ON and OFF cells with examples showing stable and un-stable phase relationships, B, C, respectively. Phase was calculated from cross-correlograms using a 5 s sliding window that was incremented by 0.5 s. Spike trains during periods of reversed phase are shown by traces in E, F. OFF alpha cells identified as sustained or transient subtypes labeled OFFS and OFFT, respectively.
Figure 5
Figure 5. Characteristic frequency of alpha and non-alpha RGCs and cross-correlogram parameters.
A. Characteristic frequency (inverse of the time interval between sequential peaks in the auto-correlogram) of rhythmic activity based on auto-correlation of spike trains recorded simultaneously from two cells, either a pair of alpha RGCs (open circles; n = 12) or a alpha and non-alpha RGC (closed squares). Solid line represents perfect correspondence between ordinate and abscissa. B. Characteristic frequencies of cell pair spike trains based on autocorrelation versus cross-correlation for same cell pairs as in A. C. Column graphs of cross-correlation strength (peak-to-trough amplitude), phase and phase standard deviation for like and un-like cell type, i.e. ON vs OFF, alpha pairs (n = 8 and 4, respectively) and alpha-non-alpha pairs (n = 15), blue, gray red columns, respectively. Column whiskers indicate minimum and maximum values, bottom and top of filled section marks intra-quartile range with boundaries at 1/4 of values equal to or less than 25th quartile and 3/4 values equal to or less than 75th quartile, respectively. Horizontal line is the mean of all values in each category.
Figure 6
Figure 6. Paired recording versus distance.
A. Schematic showing spatial relationship of recordings made with a stationary electrode in alpha RGC A (blue) paired with recordings made sequentially from 6 other cells (alpha cells gray, non-alpha cell red) in order of (a) to (f). B. Cross-correlograms of spike trains recorded from each of the six pairs. Record lengths (s) were (A to F):120, 151, 181, 121, 211, 301. In all panels black and red traces plot cross-correlations of original and shuffled spike times, respectively. The scale bar in the top panel of part B indicates the p = 0.05 level of significance for the difference between the original and shuffled traces, differences larger than the scale bar have proportionately greater levels of significance (p<0.05). C. Relationship between separation distance and cross-correlation strength, phase and phase standard deviation for all alpha/alpha (filled black circles) and alpha/non-alpha RGCs pairs (filled red squares). The slopes of linear regression lines fitted to each data set were not significantly different than zero with p values ranging from 0.13 to 0.86.
Figure 7
Figure 7. A2 amacrine cell recordings from RD1 retina slices.
A. Current clamp recording of spontaneous membrane potential (Vm) oscillations in Ames' solution (control, black trace), with addition of a cocktail of APV, DNQX, picrotoxin, strychnine (neurotransmitter antagonists, red trace), followed by added tetrodotoxin (green trace); mean Vm  = −34 mV. B. Power spectral density (PSD) of membrane potential oscillations under the same three conditions and color code. C. Oscillations persist in presence of neurotransmitter antagonists under current- (black) and voltage-clamp (red, Vhold  = −80 mV) conditions. D. Power spectra of oscillations recorded in current- (black) and voltage-clamp (red). In presence on neurotransmitter antagonist membrane potential had little effect on the amplitude of voltage oscillations (E) and no affect on their frequency (F).
Figure 8
Figure 8. Schematic diagram of electrically and chemically mediated synaptic interactions that can account for the observed results in RD1 retina.
Membrane potential oscillations (blue sinusoid) generated by a voltage-gated Na+ channel dependent mechanism originate in the network of electrically coupled A2 amacrine cells. The rhythmic fluctuations in membrane voltage cause oscillations in glycine release and strength of excitatory electrical transmission resulting in out of phase variations in membrane potential of OFF (orange sinusoid) and ON (purple sinusoid) cone bipolar cells (CBCs), respectively. The resulting variations in the strength of glutamatergic transmission stimulates oscillations in the membrane potential of: (1) OFF and ON RGCs thus accounting for out of phase generation of spike activity in un-like type RGCs (bottom raster trains) and (2) unidentified glycinergic or GABAergic amacrine cells (UACs) to give rise to oscillatory inhibitory synaptic input to alpha RGCs.
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