Es. We thank M. Chao for helpful discussions and reading the manuscript. We thank E. Nestler and T. Abel for delivering CREB knockdown tissues. We also thank Marie Monfils, Chloe Steindam, and Christi Hull for great technical help. *C.A.H. and H.W. contributed equally to this function. The authors declare no competing financial interests. Correspondence really should be addressed to Charles A. Hoeffer, Druckenmiller Neuroscience Institute, New York University College of Medicine, 550 Very first Ave., SRB 610, New York, NY 10016. E-mail: charles.hoeffer@gmail. DOI:ten.1523/JNEUROSCI.3513-12.2013 Copyright 2013 the authors 0270-6474/13/3316930-15 15.00/imminent threat (Duman and Duman, 2005). To identify the neurobiological correlates of anxiousness, genetic and pharmacological manipulations have been made use of to study anxiety-related behaviors in rodents (Gould, 2009). Typical mice show a marked preference for “unexposed” areas. The frequency and duration that mice explore exposed regions are made use of as measures of anxiety (File et al., 1990). Small is identified about the molecular substrates for anxietyrelated behavior, but studies have implicated neuronal signaling pathways that use calcium. Calcineurin (CaN) is a calcium/ calmodulin-dependent serine/threonine phosphatase with various neuronal functions, including the expression of anxiety (Manji et al., 2003; Bahi et al., 2009; Baumgartel and Mansuy, 2012). As well as calcium/calmodulin, various regulatory proteins controlling CaN activity have been identified. A single such protein is regulator of calcineurin 1 (RCAN1), which can function as both an inhibitor and facilitator of CaN activity, depending on cellular context (Kingsbury and Cunningham, 2000; Vega et al., 2002; Hilioti et al., 2004; Sanna et al., 2006). RCAN1 binds CaN and inhibits its catalytic activity (Rothermel et al., 2000; Chan et al., 2005). Also, RCAN1 can inhibit CaN by competing with substrates for the active web page (Mart ez-Mart ez et al., 2009). Conversely, RCAN1 can also mediate CaN interactionHoeffer, Wong et al. RCAN1 Modulates Anxiousness and Responses to SSRIsJ. Neurosci., October 23, 2013 33(43):16930 6944 with other proteins that facilitate CaN activity (Sanna et al., 2006; Liu et al., 2009). cAMP response element-binding protein (CREB) is another calcium-regulated protein linked to anxiousness (Pandey et al., 1999; Barrot et al., 2002; Carlezon et al., 2005; Wallace et al.Urolithin A , 2009).Amcenestrant CREB is usually a transcription element that may be regulated by reversible phosphorylation at serine-133 (S133) through several kinases and phosphatases, such as CaN (Bito et al.PMID:23892746 , 1996). A major target of CREB activity is brain-derived neurotrophic element (BDNF; Tao et al., 1998). BDNF plays a prominent role in anxiety-related behaviors in rodents (Pandey et al., 1999; Rios et al., 2001; Chen et al., 2006) and psychiatric individuals (Jiang et al., 2005; Molendijk et al., 2012). CaN regulation of those two proteins may perhaps control the manifestation of anxiety. CaN has been associated with psychiatric issues (Gerber et al., 2003) and is influenced by such drugs as selective serotonin reuptake inhibitors (SSRIs) applied to treat anxiety disorders (Crozatier et al., 2007; Rushlow et al., 2009). The connection involving CaN and anxiety led us to investigate CREB activity and anxiety-related behaviors in Rcan1 knock-out (KO) mice. We located that (1) phosphorylation of CREB and protein levels from the CREB-dependent gene Bdnf had been enhanced within the brains of Rcan1 KO mice; (two).
