Connectomic reconstruction of the human midget pathway: unexpected connectivity linked to preterm birth

Abstract

Purpose : The normal human fovea varies in morphology across individuals ranging from a large avascular zone (FAZ) with complete excavation of inner retinal layers from the foveal center to a nondescript FAZ with inner retinal layers extending across a thick foveal center (eg., Wilk et al., Vis Res 2017). Preterm birth is particularly associated with the latter morphology (e.g., Yanni et al., Br. J. Ophthal 2012) suggesting that foveal development may be altered by preterm birth. It is unknown whether this variation in foveal morphology affects the underlying neurons and circuits associated with central vision. Our purpose was to address this question directly in an adult donor retina from preterm birth using serial electron micrscopic reconstruction.

Methods : An eye from an organ donor (28 yr old male; preterm birth at 28 wks) was acquired and preserved in 4% glutaraldehyde and embedded for serial sectioning using the ATUM method (Kasthuri et al., Cell 2015). An ROI was imaged (6 nm XY resolution; 65 nm section thickness) around the foveal center extending from near the external to the internal limiting membrane. Image tiles were aligned and a tissue volume was created and all neural circuit reconstructions were made using TraKEM2 software.

Results : In this individual all retinal layers were present in the center of the foveal pit and the central most cone synaptic pedicles showed no lateral migration. We reconstructed midget bipolar cells in synaptic contact with single central cone pedicles. These midget bipolar cells made ribbon synaptic output with at least 3 ganglion cells, and several midget bipolar cells synapsed with at least 6 ganglion cells. Between 15-25% of midget bipolar cell output synapses were directed to one ganglion cell, with the remaining 75-85% of output synapses dispersed across the other ganglion cells. The midget bipolar cell output was directed primarily to midget ganglion cells (60%) however a high proportion was also directed to a distinctive large field ganglion cell type (~30%).

Conclusions : In an adult born preterm the critical microcircuitry related to the central most cones is localized to the center of the foveal pit. The midget circuit in this region lacks the expected "private-line" one-to-one cone-to-ganglion cell connectivity suggesting that preterm birth can have direct effects on the development of circuits during late gestation that underlie visual function.

This is a 2020 ARVO Annual Meeting abstract.