D its spontaneity in the absence of anReceived July 23, 2012; revised Sept. 14, 2013; accepted Sept. 17, 2013. Author contributions: C.A.H., H.W., K.K.C., and B.A.R. created investigation; C.A.H., H.W., P.C., J.L., K.K.C., Y.C., C.D., N.M., and D.R.M. performed research; D.R.M. contributed unpublished reagents/analytic tools; C.A.H., H.W., P.C., J.L., and C.D. analyzed information; C.A.H., H.W., P.C., K.K.C., B.A.R., and E.K. wrote the paper. This operate was supported by the Alzheimer’s Association (Grant 12-258900; C.A.H.), Simons Foundation (C.A.H.), and National Institutes of Wellness (National Institute of Mental Health and National Institute of Neurological Problems and Stroke Grants NS034007 and CYP1 Activator supplier NS047384, E.K.; National Institutes of Overall health Grants HL097768 and HL072016, B.A.R.). This function was also supported by the technical help in the New York University Workplace of Veterinary Services. We thank M. Chao for valuable discussions and reading the manuscript. We thank E. Nestler and T. Abel for delivering CREB knockdown tissues. We also thank Marie CB2 Antagonist Molecular Weight Monfils, Chloe Steindam, and Christi Hull for great technical help. C.A.H. and H.W. contributed equally to this operate. The authors declare no competing financial interests. Correspondence needs to be addressed to Charles A. Hoeffer, Druckenmiller Neuroscience Institute, New York University College of Medicine, 550 Initially 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 anxiety, genetic and pharmacological manipulations happen to be made use of to study anxiety-related behaviors in rodents (Gould, 2009). Standard mice show a marked preference for “unexposed” places. The frequency and duration that mice explore exposed locations are used as measures of anxiousness (File et al., 1990). Small is recognized regarding the molecular substrates for anxietyrelated behavior, but research have implicated neuronal signaling pathways that use calcium. Calcineurin (CaN) is actually a calcium/ calmodulin-dependent serine/threonine phosphatase with quite a few neuronal functions, which includes the expression of anxiousness (Manji et al., 2003; Bahi et al., 2009; Baumgartel and Mansuy, ?2012). Along with calcium/calmodulin, numerous regulatory proteins controlling CaN activity have already been identified. A single such protein is regulator of calcineurin 1 (RCAN1), which can function as each an inhibitor and facilitator of CaN activity, based 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 internet site (Mart ez-Mart ez et al., 2009). Conversely, RCAN1 can also mediate CaN interactionHoeffer, Wong et al. ?RCAN1 Modulates Anxiety 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 a different calcium-regulated protein linked to anxiety (Pandey et al., 1999; Barrot et al., 2002; Carlezon et al., 2005; Wallace et al., 2009). CREB is usually a transcription element that is certainly regulated by reversible phosphorylation at serine-133 (S133) by way of quite a few kinases and phosphatases, which includes CaN (Bito et al., 1.