Apoptosis Regulates ipRGC Spacing Necessary for Rods and Cones to Drive Circadian Photoentrainment

Abstract

SUMMARY The retina consists of ordered arrays of individual types of neurons for processing vision. Here we show that such order is necessary for intrinsically photosensitive retinal ganglion cells (ipRGCs) to function as irradiance detectors. We found that during development, ipRGCs undergo proximity-dependent Bax-mediated apoptosis. Bax mutant mice exhibit disrupted ipRGC spacing and dendritic stratification with an increase in abnormally localized synapses. ipRGCs are the sole conduit for light input to circadian photoentrainment, and either their melanopsin-based photosensitivity or ability to relay rod-cone input is sufficient for circadian photoentrainment. Remarkably, the disrupted ipRGC spacing does not affect melanopsin-based circadian photoentrainment, but severely impairs rod/cone-driven photoentrainment. We demonstrate reduced rod-cone driven cFos activation and electrophysiological responses in ipRGCs, suggesting that impaired synaptic input to ipRGCs underlies the photoentrainment deficits. Thus, for irradiance detection, developmental apoptosis is necessary for the spacing and connectivity of ipRGCs that underlie their functioning within a neural network.

Programmed Cell Death in Neurodevelopment

“…To evaluate the precise contribution of PCD to brain cell number regulation during development, lineagetracing experiments that can specifically label progeny of each cell lineage might be effective in tracing and comparing their respective fate with and without the possibility of cell death, as has been performed in previous studies in mouse (Chen et al, 2013;Nonomura et al, 2013). One would also expect that such approaches will reveal the identity of dying cells and thereby help address how early PCD is induced in and contributes to mammalian brain development.…”

“…The importance of PCD in proper spacing between cells is exemplified in visual system development both in invertebrates and vertebrates (Chen et al, 2013). The Drosophila compound eye is composed of 750 ommatidia.…”

“…Likewise, during the development of the retina in mouse, many of intrinsically photosensitive retinal ganglion cells (ipRGCs), which contain melanopsin and function for circadian rhythms and papillary light responses, undergo Bax-dependent apoptosis (Chen et al, 2013). Bax mutant exhibits a 3.7-fold increase in density of ipRGCs and thereby shows disrupted ipRGC spacing, dendritic stratification, and ectopic synapses.…”

Adverse Outcome Pathway on chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities

“…In vivo, two-photon Ca2+ imaging using Ca2+-sensitive fluorescent indicators that measure changes in intracellular Ca2+ concentration as a readout for suprathreshold and subthreshold neuronal activity has also been used to study learning and memory in live rodents (Chen et al, 2013) The last two decades the neuronal function of the larval and adult zebrafish has been extensively studied using Ca2+ imaging methods. By applying simple Ca2+ indicators such as dextran or acetoxymethyl esters to more powerful genetically encoded Ca2+ indicators, zebrafish provides a transparent model where live Ca2+ imaging can be successfully achieved (Kettunen, 2012).…”

Auditory/Visual Integration Assessment and Treatment in Brain Injury Rehabilitation

“…However, it is known that those cells are affected by both intrinsic and extrinsic signals (from rods and cones as well as from circadian functions) [38]. It has been hypothesized that the ipRGCs may be involved in heart rate regulation [39], and that they support spatial visual perception and luminance [40].…”