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Intrinsic oscillatory activity arising within the electrically coupled AII amacrine–ON cone bipolar cell network is driven by voltage‐gated Na + channels
Author(s) -
Trenholm Stuart,
Borowska Joanna,
Zhang Jiawei,
Hoggarth Alex,
Johnson Kyle,
Barnes Steven,
Lewis Timothy J.,
Awatramani Gautam B.
Publication year - 2012
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2011.225060
Subject(s) - amacrine cell , retina , hyperpolarization (physics) , biophysics , neuroscience , gap junction , chemistry , physics , biology , intracellular , biochemistry , stereochemistry , nuclear magnetic resonance spectroscopy
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.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 ( I h ), voltage‐gated Na + channels and gap junctions in mediating such oscillatory activity. Blocking I h (1 m m Cs + ) hyperpolarized the network and augmented activity, while antagonizing voltage‐dependent Na + channels (1 μ m 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 μ m 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 μ m NBQX and 50 μ m 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.