Anatomy and spatial organization of Müller glia in mouse retina

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The mammalian retina is a stratified sheet of neural tissue comprising three layers of cell bodies separated by two layers of synapses. The neural circuits of the retina are organized in both the radial (vertical through the thickness of the retina) and tangential (horizontal, parallel to the retinal surface) planes. Radially, photoreceptors located in the outer nuclear layer (ONL) send information across layers to multiple downstream target neurons that act in parallel to process distinct aspects of the visual scene. These parallel circuits are then duplicated tangentially, across the extent of the retina, to build the visual field (Kay & Sanes, 2014; Wassle & Boycott, 1991). The organization of neurons in these two planes is accompanied by similar patterning of Müller glia, the most numerous glial cell type in the retina. These cells play a vital role in maintaining the health and integrity of the retinal tissue. Like protoplasmic astrocytes in the brain, Müller glia have diverse physiological functions including regulation of synapse development, neurovascular coupling, electrolyte balance, and cellular metabolism (Vecino, Rodriguez, Ruzafa, Pereiro, &Sharma, 2016). Müller glia also make important contributions to the structural integrity of the retina. Because of their crucial roles, Müller glia must be present in sufficient number at each retinotopic location, and in each layer, to support the function of the retinal circuitry at that position. However, much remains unknown about how individual Müller glia and the population as a whole are apportioned in the retinal volume. Understanding the anatomical arrangement of Müller glia in the adult retina, and how it arises during development, will provide important insight into the specific interactions between Müller glia and neurons that support visual function.
The morphology of Müller glia has been studied using Golgi impregnation and immunohistochemistry in a variety of vertebrate species, including rabbit, tree shrew, turtle, horse, rat, and mouse (Drager, Edwards, & Barnstable, 1984; Dreher, Robinson, & Distler, 1992; Reichenbach & Wohlrab, 1983; Robinson & Dreher, 1990). From these studies we know that Müller cells have a conserved bipolar morphology in the radial plane. Their somas reside at the center of the middle cell body layer, the inner nuclear layer (INL), from which radially oriented processes emerge to span the thickness of the neuroretina. As they traverse the retina, Müller glia adopt a distinct morphology at each retinal layer: (1) conically branching endfeet densely ensheathe neurons and blood vessels in the ganglion cell layer (GCL) and form the inner limiting membrane (ILM); (2) fine processes ramify in both synaptic layers, the inner and outer plexiform layers (IPL and OPL); (3) the vertical stalk divides to weave through the ONL, surrounding photoreceptor cell bodies and forming the outer limiting membrane (OLM); and (4) microvilli extend past the OLM to associate tightly with photoreceptor inner segments. The remarkable subcellular specialization of Müller glia across retinal layers presumably reflects the distinct functions they perform at each layer. For example, they subserve crucial structural roles at the limiting membranes, and in the plexiform layers they support synaptic function in a manner similar to brain protoplasmic astrocytes (Allen, 2014; Clarke & Barres, 2013; Rasmussen, 1972; Reichenbach & Bringmann, 2013; Reichenbach et al., 1989; Vecino et al., 2016). Given that the IPL can be further divided into sublaminae containing various types of synapses with different functions (Sanes & Zipursky, 2010), it is possible that Müller glia may also display sublaminar specializations that have previously not been appreciated.
In the tangential plane, Müller glia spatial patterning manifests in the retinotopic distribution of their cell bodies, the arborization of single cells, and the relationship between territories of neighboring cells.
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