Cell‐ and region‐specific expression of depression‐related protein p11 (S100a10) in the brain

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P11, also known as S100A10, calpactin I light chain, or annexin II light chain, is a protein that forms a heterotetramer complex with annexin A2 (Anxa2) (Gerke et al., 2005; Oh et al., 2013). This complex interacts with multiple types of receptors (Svenningsson et al., 2006; Warner‐Schmidt et al., 2009), ion channels (Girard et al., 2002; Okuse et al., 2002; Donier et al., 2005), and enzymes (Le Bouffant et al., 1998; Mai et al., 2000; Zobiack et al., 2003). The p11/Anxa2 heterotetramer complex is involved in the organization of lipid microdomains on the cell membrane, bundling of actin filaments and cytoskeleton scaffolding, membrane trafficking, and fibrinolysis (Babiychuk and Draeger, 2000; Menke et al., 2005; Hayes et al., 2006; Surette et al., 2011). Although expressed in many organs, including the heart, kidneys, liver, lungs, spleen, testes, epidermis, aorta, thymus, gastrointestinal tract, and brain (Zimmer et al., 2005), little is known about the specificity of p11 expression within these organs. In addition to neurons, the expression of p11 has been confirmed in circulating monocytes/macrophages, endothelial cells in blood vessel walls, reactive astrocytes, splenocytes, fibroblasts, and tumor cells (Gerke et al., 2005; Dassah et al., 2009; Madureira et al., 2012; Zamanian et al., 2012; Svenningsson et al., 2014).
The p11/Anxa2 system is involved in many diseases, such as thrombosis, atherosclerosis, retinopathy, pain perception, and cancer, as well as in neuropsychiatric diseases (Hedhli et al., 2012). Recently, the role of p11 in major depressive disorder (MDD) has garnered interest. A role for p11 in human neuropsychiatric disorders has been suggested in clinical studies (Anisman et al., 2008; Zhang et al., 2011a; Svenningsson et al., 2014). It was reported that patients with MDD and posttraumatic stress disorder have decreased levels of p11 in the brain (Svenningsson et al., 2006; Anisman et al., 2008; Alexander et al., 2010; Zhang et al., 2011b). Furthermore, p11 levels in white blood cells can predict a patient's response to antidepressants during the initial phase of treatment (Svenningsson et al., 2014). We have shown that the constitutive knockout of p11 in mice (p11‐KO) results in a depressive‐like phenotype (Svenningsson et al., 2006); this effect is replicated in region‐ and cell‐specific knockouts (Alexander et al., 2010; Warner‐Schmidt et al., 2012). Moreover, the p11 expressing cells in cortical layer 5a, and in mossy cells in the dentate gyrus, are critical for response to antidepressants, while those in the nucleus accumbens are not (Schmidt et al., 2012; Warner‐Schmidt et al., 2012; Oh et al., 2013).
Taken together, these data point to a key role for p11 in MDD, but widespread expression in the brain makes it difficult to determine a unifying mechanism of p11 action. At present, it appears that p11‐dependent changes in behavior vary in different regions and cell types, and are affected by the circuitry of each cell type. We and others have previously explored the role of p11 in MDD by examining individual neuronal subtypes, distinguished by position, neurotransmitter, and connectivity, and analyzing its mechanism of action in several areas, such as the cortex, nucleus accumbens, and hippocampus (Alexander et al., 2010; Schmidt et al., 2012; Warner‐Schmidt et al., 2012; Oh et al., 2013; Lee et al., 2015). Other areas potentially important for the pathophysiology of depression such as the amygdala or midbrain monoaminergic nuclei, on the other hand, were not. To accomplish this, a detailed mapping of p11 expression is required. Here we provide the cell‐ and region‐specific expression data of p11 in the adult mouse brain as revealed by in situ hybridization and immunofluorescence on tissue sections, as well as by immunolabeling enabled 3D imaging of solvent‐cleared organs (iDISCO).
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