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Nonlinear dendritic integration of electrical and chemical synaptic inputs drives fine-scale correlations

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Throughout the CNS, gap junction–mediated electrical signals synchronize neural activity on millisecond timescales via cooperative interactions with chemical synapses. However, gap junction–mediated synchrony has rarely been studied in the context of varying spatiotemporal patterns of electrical and chemical synaptic activity. Thus, the mechanism underlying fine-scale synchrony and its relationship to neural coding remain unclear. We examined spike synchrony in pairs of genetically identified, electrically coupled ganglion cells in mouse retina. We found that coincident electrical and chemical synaptic inputs, but not electrical inputs alone, elicited synchronized dendritic spikes in subregions of coupled dendritic trees. The resulting nonlinear integration produced fine-scale synchrony in the cells' spike output, specifically for light stimuli driving input to the regions of dendritic overlap. In addition, the strength of synchrony varied inversely with spike rate. Together, these features may allow synchronized activity to encode information about the spatial distribution of light that is ambiguous on the basis of spike rate alone.

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Figure 1: Gap junctions between ganglion cells mediate fine-scale correlated activity.
Figure 2: Simulated coupled spikelets do not act at the soma to drive correlated spiking.
Figure 3: Gap junction inputs on their own do not trigger dendritic spikes.
Figure 4: Dendritic spikes appear to mediate gap junction–dependent fine-scale synchronization.
Figure 5: Gap junction–mediated correlations are spatially restricted to overlapping dendritic regions.
Figure 6: Correlation strength varies inversely with spike rate.
Figure 7: Correlated action potentials carry information that is independent of the spike rate.

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We thank K. Delaney, A. Pereda and S. Sethuramanujam for their helpful comments on this manuscript, D. Paul for kindly providing the Cx36−/− mice, J. Boyd (University of British Columbia) for his help in writing software for two-photon imaging, and A. Sullivan for maintaining mouse colonies. This work was supported by US National Institutes of Health grants R01-EY022070 (R.G.S.) and R01-EY11850 (F.R.), National Eye Institute grant EY07031 (M.H.T.), the Howard Hughes Medical Institute (F.R.), and by the Canadian Institutes of Health Research (130268-2013, G.B.A.) and Foundation for Fighting Blindness (Canada, G.B.A.).

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This study was designed by S.T., D.J.S., A.J.M., F.R., M.H.T. and G.B.A. All of the experiments were performed by S.T. and A.J.M. (except for those presented in Fig. 2d–f, which were performed by M.H.T.). The results were analyzed by S.T., A.J.M., M.H.T. and D.J.S. The paper was written by S.T., D.J.S., M.H.T., F.R., R.G.S. and G.B.A.

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Correspondence to Gautam B Awatramani.

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Integrated supplementary information

Supplementary Figure 1 Broad stimulus-driven and fine-noise correlations in cRGCs.

a, A cross-correlogram from the same pair of cells shown in Fig. 1d, but shown on a broader timescale (± 100ms) to reveal slower stimulus driven correlations. b, The same raw cross correlogram as shown in Fig. 1d (left), as well as the shuffled trials shift predictor (middle) and the shift-predictor subtracted (right, Corrected) correlations.

Supplementary Figure 2 Fine-scale gap junction–mediated correlations are present for both ON and OFF responses of cRGCs.

a, A raster plot of the light-evoked spiking response (5 repeats are shown) of a pair of cRGCs (C1-red and C2-blue) to a high contrast flash of light (indicated on bottom). b, Cross-correlograms for both ON (left) and OFF (middle) responses exhibit fine-scale correlations. For data presented in the paper, we pooled data from ON and OFF responses (right).

Supplementary Figure 3 Pharmacologically blocking gap junctions inhibits fine-scale correlations, but does not block broad timescale stimulus-dependent correlations.

a, Control (left) and 18β-glycyrrhetinic acid (18βGA, 25 µM, right) treated responses from a pair of cRGCs. The top traces represent 4 trails of drifting gratings moving above a pair of neighbouring cRGCs (C1, red = cell 1; C2, blue = cell 2). Gaussian fits of the spike rate are plotted below. b, Cross-correlograms for the relevant control and 18βGA treated responses. The zoom in (bottom left) shows that the peak in the correlogram is a fine-scale correlation at < ± 2 ms, which is eliminated with application of 18βGA, while broad timescale stimulus driven correlations persist.

Supplementary Figure 4 Uncoupled RGCs do not exhibit fine-scale correlations.

a, A cross-correlogram (± 200 ms), showing the broad, stimulus driven correlation between a pair of uncoupled directionally selective ganglion cells. Note the absence of an additional fine-scale peak in the graph at ± ~2 ms.

Supplementary Figure 5 Coupling between cRGCs and fine-scale correlations are reduced in Cx36 knockout retina.

a, Example paired current clamp recordings from wt (top) and Cx36 knockout retina (bottom). The cartoon (top left) shows the experimental paradigm, where hyperpolarizing and depolarizing currents are injected into cell 1 (black). The change in membrane potential upon current injection into C1 is plotted for C1 (left, black) and C2 (right, red). Note that the amount of voltage change driven by gap junctions in C2 is reduced in Cx36 knockout. b, Plots of cross-correlograms for light evoked spike activity in cRGCs in wildtype retina (top) and Cx36 knockout retina (bottom), revealing that correlated spiking is greatly reduced in the absence of Cx36.

Supplementary Figure 6 Depolarization induced correlations persist in a cocktail of synaptic receptor blockers.

a, The light response of a cRGC in control conditions (top) and in the presence of a cocktail of synaptic receptors blockers (bottom). The cocktail included: NBQX (20 µM, to block AMPA/Kainate receptors), AP5 (50 µM, to block NMDA receptors), tubocurare (50 µM, to block acetylcholine receptors), L-AP4 (50 µM, to block mGluR6 receptors), picrotoxin (50 µM, to block GABAA receptors), TPMPA (50 µM, to block GABAC receptors) and strychnine (5 µM, to block glycine receptors). The yellow bars indicate the duration of the light stimulus. b, Shows the correlated spiking responses of a pair of cRGCs when simultaneously depolarized by ~10 mV through the patch electrode (top). The bottom trace is a higher magnification view of the area show in grey. c, A cross-correlogram computed for the spike trains shown in (b). Note, as with the light response, the size of the bimodal peaks varied for different pairs, likely due to a combination factors including differences in the level of depolarization between two cells, the precise properties of the dendro-dendritic connections (which could potentially give rise to impedance mismatches) and intrinsic excitability.

Supplementary Figure 7 Dendritic spikes are revealed by hyperpolarizing the soma through the patch electrode.

a, The light response of a cRGC is shown in control (top) and when hyperpolarized with a -150 pA current injection (bottom). b, The area highlighted in grey in (a) is shown at higher resolution (top). Plotting dV/dt allows the clear differentiation between single dendritic spikes (left), multiple dendritic spikes that sum (note that dendritic spikes do not to have a refractory period; middle, grey arrow) and somatic action potentials (right).

Supplementary Figure 8 Local dendritic application of TTX does not affect the shape of somatic action potentials.

a, A diagram outlining the experimental protocol, in which TTX is locally puffed over the overlapping dendritic regions between two neighbouring cRGCs. b, The average spike shapes for a pair of cRGCs before (blue) and during (red) dendritic TTX application.

Supplementary Figure 9 Detecting dendritic spikes by inhibiting somatic Na+ channels.

a, Intracellular recording of responses of a cRGC to drifting gratings while TTX was puffed locally over the soma reveals dendritic spikes (asterisks) and larger spike like events that represent incompletely blocked somatic spikes (see Oesch et al., 2005 for similar results in the rabbit retina). b, The time derivative of the voltage trace shown in (a). Events with peak amplitudes falling between the blue dotted lines were unequivocally identified as dendritic spikes and chosen for cross-correlation analysis (Fig. 4d in main text). Larger events that potentially could have arisen from the soma (due to the incomplete block of somatic Na+ channels by TTX) were discarded in this analysis. c, A histogram of the peak amplitude of spike-like events during somatic TTX application (>500 events).

Supplementary Figure 10 Dendritic spikes in post-junctional cells are synchronized with somatic action potentials in pre-junctional cells.

a, An average cross-correlogram, from 4 pairs, of the relationships between somatic spikes in one cell and dendritic spikes in a coupled neighbor (the red line indicates the 95% confidence interval). Somatic action potentials in cell 1 are set at time 0, meaning that peaks at positive time values represent dendritic spikes in cell 2 that consistently occurred after somatic action potentials in cell 1.

Supplementary Figure 11 Both common and uncommon inputs drive broad stimulus-driven correlations, but not fine-scale correlations.

a, A diagram of the experimental paradigm, where cells are either driven with a spot that stimulates common input (spot 1) or with two spots that stimulate uncommon inputs (spots 2+3). b, A cross-correlogram for a pair of cRGCs receiving common input. c, A cross-correlograms the same pair of cRGCs receiving uncommon input. This pair is the same pair shown in Fig. 5d.

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Trenholm, S., McLaughlin, A., Schwab, D. et al. Nonlinear dendritic integration of electrical and chemical synaptic inputs drives fine-scale correlations. Nat Neurosci 17, 1759–1766 (2014).

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