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A Method for High Fidelity Optogenetic Control of Individual Pyramidal Neurons In vivo

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Gain control by sparse, ultra-slow glycinergic synapses.

Varsha Jain¹, Laura Hanson¹, Santhosh Sethuramanujam¹

¹Department of Biology, University of Victoria, Victoria, BC V8W 3N5 Canada.

|February 23, 2022

Summary

Starburst amacrine cells (SACs) use slow, summating glycinergic inhibition, not GABAergic, to compute visual direction. This unexpected finding reveals novel amacrine cell roles in retinal circuits.

Keywords:

GABA inhibition GRAB-ACh3.0 alpha4 glycine receptors direction selectivity direction-selective ganglion cell inhibitory neural circuitry narrow-field amacrine cells retina serial block-face electron microscopy starburst amacrine cells

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Area of Science:

Neuroscience
Retinal circuitry
Visual processing

Background:

ON starburst amacrine cells (SACs) are key to direction-selective retinal circuits.
The sources of inhibition shaping SAC responses were previously unclear.
Most SAC inhibitory synapses were thought to be GABAergic.

Purpose of the Study:

To identify the sources and nature of inhibitory currents in SACs.
To understand how inhibition shapes SAC function in direction selectivity.
To elucidate the role of specific amacrine cells in retinal computation.

Main Methods:

Electrophysiological recordings to measure light-evoked currents in SACs.
Pharmacological identification of neurotransmitter receptor involvement.
Serial electron microscopy for ultrastructural analysis and cell reconstruction.
Analysis of synaptic connections between amacrine cells and SACs.

Main Results:

Light-evoked inhibitory currents in SACs are predominantly glycinergic, contrary to prior assumptions.
Glycinergic inhibition is slow, mediated by non-canonical glycine receptors (α4 subunits).
Glycine inputs originate from both ON and OFF retinal pathways.
Three types of narrow-field amacrine cells are identified as the likely sources of glycinergic inhibition.
Glycine receptor properties allow for summation, controlling SAC output gain and expanding directional computation range.

Conclusions:

Glycinergic inhibition, rather than GABAergic, plays a critical role in shaping SAC responses.
Specific glycinergic amacrine cells are essential for retinal direction computation.
The slow kinetics and summation properties of glycine inputs are crucial for SAC function in direction selectivity.