Eye-specific retinogeniculate segregation proceeds normally following disruption of patterned spontaneous retinal activity.

Colenso M Speer,Barbara Chapman,Lauren C Liets,Chao Sun,Ben K Stafford,Hwai-Jong Cheng

doi:10.1186/1749-8104-9-25

Abstract

BackgroundSpontaneous retinal activity (SRA) is important during eye-specific segregation within the dorsal lateral geniculate nucleus (dLGN), but the feature(s) of activity critical for retinogeniculate refinement are controversial. Pharmacologically or genetically manipulating cholinergic signaling during SRA perturbs correlated retinal ganglion cell (RGC) spiking and disrupts eye-specific retinofugal refinement in vivo, consistent with an instructive role for SRA during visual system development. Paradoxically, ablating the starburst amacrine cells (SACs) that generate cholinergic spontaneous activity disrupts correlated RGC firing without impacting retinal activity levels or eye-specific segregation in the dLGN. Such experiments suggest that patterned SRA during retinal waves is not critical for eye-specific refinement and instead, normal activity levels are permissive for retinogeniculate development. Here we revisit the effects of ablating the cholinergic network during eye-specific segregation and show that SAC ablation disrupts, but does not eliminate, retinal waves with no concomitant impact on normal eye-specific segregation in the dLGN.ResultsWe induced SAC ablation in postnatal ferret pups beginning at birth by intraocular injection of a novel immunotoxin selective for the ferret vesicular acetylcholine transporter (Ferret VAChT-Sap). Through dual-patch whole-cell and multi-electrode array recording we found that SAC ablation altered SRA patterns and led to significantly smaller retinal waves compared with controls. Despite these defects, eye-specific segregation was normal. Further, interocular competition for target territory in the dLGN proceeded in cases where SAC ablation was asymmetric in the two eyes.ConclusionsOur data demonstrate normal eye-specific retinogeniculate development despite significant abnormalities in patterned SRA. Comparing our current results with earlier studies suggests that defects in retinal wave size, absolute levels of SRA, correlations between RGC pairs, RGC burst frequency, high frequency RGC firing during bursts, and the number of spikes per RGC burst are each uncorrelated with abnormalities in eye-specific segregation in the dLGN. An increase in the fraction of asynchronous spikes occurring outside of bursts and waves correlates with eye-specific segregation defects in studies reported to date. These findings highlight the relative importance of different features of SRA while providing additional constraints for computational models of Hebbian plasticity mechanisms in the developing visual system.Electronic supplementary materialThe online version of this article (doi:10.1186/1749-8104-9-25) contains supplementary material, which is available to authorized users.

Highlights

Spontaneous retinal activity (SRA) is important during eye-specific segregation within the dorsal lateral geniculate nucleus, but the feature(s) of activity critical for retinogeniculate refinement are controversial
To evaluate the role of cholinergic spontaneous retinal activity in the refinement of eye-specific projections to the dorsal lateral geniculate nucleus (dLGN), we ablated Starburst amacrine cell (SAC) beginning at birth and examined retinogeniculate central anatomy at postnatal day 10 (P10) when eye-specific segregation in the ferret dLGN is largely complete (Figure 1) [3,4]
In summary, we have shown that patterned spontaneous retinal activity can be significantly disrupted without affecting the normal development of eye-specific retinogeniculate projections

Summary

Introduction

Spontaneous retinal activity (SRA) is important during eye-specific segregation within the dorsal lateral geniculate nucleus (dLGN), but the feature(s) of activity critical for retinogeniculate refinement are controversial. The precise pattern of correlated RGC output has been hypothesized to play critical roles in visual circuit development by instructing the remodeling of retinofugal axon terminals in a retinotopic and eye-specific fashion (for a recent review discussing the role of spontaneous activity in circuit development see Kirkby et al [11]) Consistent with this hypothesis, pharmacological disruptions of cholinergic spontaneous retinal activity lead to abnormal retinogeniculate [12,13,14,15,16,17], retinocollicular [17,18,19], and geniculocortical [20,21] visual pathway development. Genetic deletion of the ß2 subunit of the nicotinic acetylcholine receptor (ß2(KO)) disrupts spontaneous retinal activity [22,23,24,25,26] and perturbs retinogeniculate [15,17,23,27,28,29], retinocollicular [17,18,19,30,31,32,33], and visual geniculocortical development [20,33,34,35]

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