Intrinsic oscillatory activity arising within the electrically coupled AII amacrine–ON cone bipolar cell network is driven by voltage‐gated Na⁺ channels

Abstract

Key points• In mouse models for retinal degeneration, photoreceptor death leads to membrane oscillation in the remnant AII amacrine-ON cone bipolar cell network through an unknown mechanism.• We found such oscillations require voltage-gated Na + channels and gap junctions but not hyperpolarization-activated currents (I h ).• Na + channels are expressed predominantly in AII amacrine cells and I h in ON cone bipolar cells, and appear to interact via gap junctions to shape oscillations.• Similar intrinsic oscillations arose in the wild-type (wt) AII amacrine-ON cone bipolar cell network when photoreceptor inputs to bipolar cells were pharmacologically occluded.• Computational modelling captures experimental findings when a low level of cellular heterogeneity is introduced in the coupled network.• These unique insights into the cellular mechanisms underlying spontaneous activity in the degenerating retina might aid in designing the most effective strategies to restore vision using retinal prosthesis. AbstractIn the rd1 mouse model for retinal degeneration, the loss of photoreceptors results in oscillatory activity (∼10-20 Hz) within the remnant electrically coupled network of retinal ON cone bipolar and AII amacrine cells. We tested the role of hyperpolarization-activated currents (I h ), voltage-gated Na + channels and gap junctions in mediating such oscillatory activity. Blocking I h (1 mM Cs + ) hyperpolarized the network and augmented activity, while antagonizing voltage-dependent Na + channels (1 μM TTX) abolished oscillatory activity in the AII amacrine-ON cone bipolar cell network. Voltage-gated Na + channels were only observed in AII amacrine cells, implicating these cells as major drivers of activity. Pharmacologically uncoupling the network (200 μM meclofenamic acid (MFA)) blocked oscillations in all cells indicating that Na + channels exert their influence over multiple cell types within the network. In wt retina, occluding photoreceptor inputs to bipolar cells (10 μM NBQX and 50 μM L-AP4) resulted in a mild (∼10 mV) hyperpolarization and the induction of oscillatory activity within the AII amacrine-ON cone bipolar cell network. These oscillations had similar properties to those observed in rd1 retina, suggesting that no major degeneration-induced network rewiring is required to trigger spontaneous oscillations. Finally, we constructed a simplified computational model that exhibited Na + channel-dependent network oscillations. In this model, mild heterogeneities in channel densities between individual neurons reproduced our experimental findings. These results indicate that TTX-sensitive Na + channels in AII amacrine cells trigger degeneration-induced network oscillations, which provide a persistent synaptic drive to downstream remnant neurons, thus appearing to replace photoreceptors as the principal drivers of retinal activity.

Dynamic Tuning of Electrical and Chemical Synaptic Transmission in a Network of Motion Coding Retinal Neurons

“…Interestingly, only a subset of ON-OFF DSGCs is electrically coupled (Vaney, 1994;Weng et al, 2005). Previously, based on electrophysiological measurements and pharmacology, we postulated that the superior coding DSGC population labeled in the Hb9::eGFP transgenic mouse retina corresponds to the electrically coupled population (Trenholm et al, 2013). Here, we confirm the presence of gap junctions using tracer-coupling methods and by analyzing depolarization-induced feedback spikelets in voltageclamped DSGCs.…”

“…Interestingly, the responses of coupled DSGCs were highly skewed toward the leading edge of the moving stimulus, indicating that gap junction signals from upstream DSGCs effectively primed responses (Trenholm et al, 2013). In contrast, the falling phase of the response did not appear to be boosted, suggesting that gap junction signals from downstream DSGCs were less effective.…”

“…A remarkable property of superior coding ON-OFF DSGCs that arises from the combination of electrical and chemical synaptic signaling is the ability to normalize spatial lags that arise from transmission delays (i.e., these cells can detect moving edges at a constant retinal location regardless of stimulus velocity; Trenholm et al, 2013). Interestingly, the responses of coupled DSGCs were highly skewed toward the leading edge of the moving stimulus, indicating that gap junction signals from upstream DSGCs effectively primed responses (Trenholm et al, 2013).…”

“…While gap junction inputs alone appeared to be ineffective in driving spike activity in neighboring cells, our previous findings suggested that coupled DSGCs could prime their neighbors by sensitizing the bipolar cell-DSGC synapse (Trenholm et al, 2013). To directly test this idea, we made paired current-clamp recordings from adjacent coupled DSGCs [cell 1 (C1) and cell 2 (C2)] and (1) stimulated subthreshold bipolar cell inputs to C2 using low-contrast light flashes (Fig.…”

“…Activity can either modify the properties of the gap junctions themselves (Zsiros and Maccaferri, 2008;Haas et al, 2011;Kothmann et al, 2012) or modulate the efficacy of electrical signaling indirectly through changes in membrane properties (Llinas et al, 1974;Mann-Metzer and Yarom, 1999;Curti et al, 2012;Trenholm et al, 2012). However, as most gap junction studies have used in vitro preparations where natural patterns of activity are not preserved, the dynamics of chemical-electrical signaling during specific neural computations remain poorly understood.…”