br Distribution of OCT in rat
Distribution of OCT3 in rat brain To understand the potential roles of this corticosterone-sensitive monoamine clearance mechanism in the regulation of monoaminergic neurotransmission and behavior, and its potential contribution to corticosteroid actions on behavior, we examined the rostrocaudal distribution of OCT3 in the male rat Retapamulin sale using immunohistochemistry (Gasser et al., 2009). The transporter is expressed, at least at low levels, in nearly all brain regions. It is found in white matter tracts, where it occurs in cells morphologically similar to oligodendrocytes, and broadly in grey matter areas. Perikarya expressing OCT3 are found in ependymal and subependymal cells lining the ventricles. The transporter is densely expressed in granule cell neurons, including those in the cerebellum, olfactory bulb, subventricular zones, and retrosplenial cortex. This is consistent with studies demonstrating that OCT3 mediates the uptake of the neurotoxin MPP+ in cultured cerebellar granule neurons (Shang et al., 2003). High densities of OCT3-expressing fibers and/or cells are also found in circumventricular zones, including the subcommissural organ, vascular organ of the lamina terminalis, area postrema, and median eminence (Gasser et al., 2009; Vialou et al., 2004). An important question for future research is whether or not OCT3 (and/or OCT1 or OCT2) is expressed in tanycytes, which have been implicated in transport of signaling molecules between neurons and extra-neuronal spaces, the cerebrospinal fluid, and the hypothalamic-hypophyseal portal circulation (Goodman and Hajihosseini, 2015), or other monoamine-accumulating ependymal and subependymal cells that have been identified in the rodent medial hypothalamus (Lowry et al., 1996). Tanycytes contain monoamines, including serotonin (Sladek, Jr. and Sladek Jr and Sladek, 1978), have been implicated in hypothalamic glucosensing (Elizondo-Vega et al., 2015) and have recently been identified as a population of neural progenitor cells within appetite/energy-balance regulating centers of the postnatal and adult hypothalamus (Goodman and Hajihosseini, 2015; Haan et al., 2013). Studies examining the cellular and subcellular distributions of OCT3 suggest that this transporter plays a variety of roles in regulating monoaminergic neurotransmission. Expression of OCT3 has been demonstrated in neurons (Cui et al., 2009; Gasser et al., 2009; Hill et al., 2011; Shang et al., 2003; Vialou et al., 2004), astrocytes (Cui et al., 2009; Gasser et al., 2017; Takeda et al., 2002), microglia (He et al., 2017), oligodendrocytes (Gasser et al., 2009), ependymal (Gasser et al., 2006; Gasser et al., 2009) and vascular endothelial cells (Li et al., 2013) in the brain. Thus, OCT3 is positioned to regulate extracellular monoamine concentrations in a variety of microenvironments in the central nervous system. The exact role of OCT3 in regulation of monoaminergic neurotransmission depends critically on the subcellular localization of the transporter, particularly with respect to transmitter release sites and receptors. In a recent study, we used immunofluorescence and immunoelectron microscopy to identify the cellular and subcellular distribution of OCT3 within the amygdala of both rats and mice (Gasser et al., 2017). Dense OCT3 immunoreactivity was observed in plasma membranes of both neurons and astrocytic glial cells. The transporter was observed in neuronal somata, as well as in axonal and dendritic membrane profiles, suggesting that OCT3 may regulate the extent to which monoamines activate pre- and post-synaptic receptors, and therefore the neuromodulatory effects of monoamines. Interestingly, many of the OCT3-expressing axonal profiles displayed structural characteristics of noradrenergic terminals, indicating that presynaptic reuptake of norepinephrine may involve OCT3 as well as the norepinephrine transporter (NET). Dense OCT3 expression was also observed in the plasma membranes of astrocyte processes that ensheathed both axospinous and axodendritic processes, suggesting another mechanism by which OCT3 may modulate monoaminergic transmission.