Melanopsin expressing human retinal ganglion cells: Subtypes, distribution, and intraretinal connectivity
Intrinsically photosensitive retinal ganglion cells (ipRGCs) belong to the most recently identified cell types in the mammalian retina (Do & Yau, 2010). The ipRGCs express melanopsin photoreceptor protein on the cell surface, which after activation by light initiates neuronal signals to the brain concerning environmental light intensities (Do & Yau, 2010). This light information is used to regulate several so‐called nonimage forming (NIF) tasks such as entrainment of the circadian timing system, negative masking behavior of locomotor activity, pupillary light reflex (Hattar et al., 2003; Schmidt, Chen, & Hattar, 2011a), and the sleep/wake induction (Lupi, Oster, Thompson, & Foster, 2008; Tsai et al., 2009). More recent studies have provided evidence that ipRGCs also contribute to pattern vision (Brown et al., 2010; Ecker et al., 2010; Estevez et al., 2012; Procyk et al., 2015). Since the identification of melanopsin in a subpopulation of retinal ganglion cells, knowledge of their diversity has expanded anatomically and functionally (Schmidt et al., 2011a). In mice and in rats, ipRGCs are represented by five subtypes (M1–M5)(Reifler et al., 2015; Schmidt et al., 2011a). Based on localization and dendritic projections, M1 cells have their soma located either in the ganglion cell layer (GCL) or displaced in the inner nuclear layer (INL) with dendritic stratification in the outermost (OFF) layer (S1) of the inner plexiform layer (IPL). M2, M4 and M5 cells have cell bodies exclusively in GCL and dendritic stratification in the innermost (ON) layer of the IPL (S5), while M3 cells have their cell bodies in the GCL with dendritic stratification in both S5 and S1 (Cui, Ren, Sollars, Pickard, & So, 2015; Reifler et al., 2015; Schmidt et al., 2011a). In primates, including humans, melanopsin immunoreactive (ir) RGCs have so far been classified as inner and outer stratifying cells, where outer stratifying cells represent M1 cells, and inner stratifying cells seem to represent M2 cells (Dacey et al., 2005; Hannibal et al., 2004; Jusuf, Lee, Hannibal, & Grunert, 2007; Liao et al., 2016). Immunohistochemical staining in both rodent and primate retina revealed that the level of melanopsin expression varies within the different subtype of ipRGCs. There is evidence from studies in rodents that melanopsin expression is regulated both by light and by a circadian clock (Hannibal, Georg, & Fahrenkrug, 2007; Hannibal, Georg, Hindersson, & Fahrenkrug, 2005). The existence of two different isoforms of melanopsin and their expression level and detection contribute significantly to observations, that M1 subtypes of ipRGCs have a general higher level of melanopsin compared to the remaining subtypes. In mice, M1 cells express a short form of melanopsin (Opn4S) which is 40 times more abundant than the long form of melanopsin (Opn4L), which also occurs in M1 cells while Opn4L is the only form found in M2 cells (Hughes et al., 2012; Pires et al., 2009).
The different subtypes of melanopsin‐ir RGCs have in mice been shown to innervate brain areas responsible for specific NIF functions (Baver, Pickard, Sollars, & Pickard, 2008; Chen, Badea, & Hattar, 2011; Ecker et al., 2010). M1 cells can be characterized not only by anatomical criteria, but also whether they express Brn3b (Chen et al., 2011). Using mice ablated for melanopsin/Brn3b ipRGCs, Chen et al. showed that M1 cells lacking Brn3b primarily innervate the suprachiasmatic nucleus (SCN), known as the brain's master clock, while melanopsin‐ir RGCs expressing Brn3b innervate other areas including the olivary pretectal nucleus (OPN) involved in the pupillary light reflex. Accordingly, mice lacking the melanopsin/Brn3b containing ipRGCs display a severely disrupted pupillary response but intact circadian regulation (Chen et al., 2011).