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

S Trenholm, J Borowska, J Zhang… - The Journal of …, 2012 - Wiley Online Library
S Trenholm, J Borowska, J Zhang, A Hoggarth, K Johnson, S Barnes, TJ Lewis
The Journal of physiology, 2012Wiley Online Library
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 (Ih).• Na+ channels are
expressed predominantly in AII amacrine cells and Ih in ON cone bipolar cells, and appear
to interact via gap junctions to shape oscillations.• Similar intrinsic oscillations arose in the …
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 (Ih).
  • • 
    Na+ channels are expressed predominantly in AII amacrine cells and Ih 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.
Abstract  In 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 (Ih), voltage‐gated Na+ channels and gap junctions in mediating such oscillatory activity. Blocking Ih (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.
Wiley Online Library