Alternatively, mice expressing the Y1472F mutation of GluN2B show a selective impairment in amygdala-dependent fear-learning [13]. anxiety-like Acetylcorynoline behavior by negative regulation of CRF expression in the amygdala. == Background == Anxiety is commonly experienced and typically adaptive; however, excessive and dysfunctional anxiety leads to serious disorders. Anxiety disorders are the most prevalent class of psychiatric disorders in many countries [1]. Compounds that target of -aminobutyric acid and the serotonergic systems have received great attention within the development of treatments for anxiety disorders [2]. As some forms of anxiety are relatively resistant to treatment with these compounds, which include benzodiazepines and selective serotonin reuptake inhibitors, it has become increasingly apparent that alternative Acetylcorynoline treatment strategies are needed. Recently, the glutamatergic system, the major mediator of excitatory synaptic transmission in the mammalian brain, has been the focus of pathophysiological studies of human anxiety disorders [3]. In rodents,N-methyl-D-aspartate (NMDA) receptor antagonists show anxiolytic effects in several test scenarios including the elevated plus-maze test [4,5]. While these reports point to the involvement of NMDA receptor-mediated signaling in the regulation of anxiety-like behaviors, molecular dissection of the role of NMDA receptor-mediated signaling is difficult because glutamate exerts its effects on various neural functions in a highly complex manner [6]. The NMDA receptor is crucial for neural development, synaptic plasticity, neuronal excitotoxicity, and behavior [6-9]. The NMDA receptor is composed of the GluN1 and GluN2 subunits: the GluN1 subunit is essential for the function of NMDAR channels, whereas the GluN2 subunits (GluN2A, GluN2B, GluN2C, and GluN2D) determine the characteristics of NMDAR channels by forming different heteromeric configurations with the GluN1 subunit [6]. The function of NMDA receptor-mediated signaling is in part regulated by Src tyrosine kinase-mediated phosphorylation of the GluN2 subunit [10,11]. Previous studies have found that Tyr-1325 and Tyr-1472 are the principal tyrosine phosphorylation sites on the GluN2A Acetylcorynoline and the GluN2B subunits, respectively [12,13]. Genetically engineered mice expressing the Y1325F mutation of GluN2A show antidepressant-like behavior, but their other neural functions, such as hippocampal-dependent learning, are normal [12]. Alternatively, mice expressing the Y1472F mutation of GluN2B show a selective impairment in amygdala-dependent fear-learning [13]. Considering the versatile role of the NMDA receptor in various neural functions [6], the phenotypes Rabbit polyclonal to KIAA0494 of these mutant mice are milder than expected: thus these mice provide valuable models in which to dissect the molecular basis of specific behaviors including anxiety-like behavior. Corticotropin-releasing factor (CRF), which is highly abundant in the amygdala as well as in the paraventricular nucleus of the hypothalamus, plays an important role in regulating anxiety-like behavior [14]. Patients suffering from anxiety disorders often have increased CRF levels in their cerebrospinal fluid [15,16]. In rodents, intracerebro-ventricular delivery of CRF is anxiogenic [17]. Likewise, transgenic mice overexpressing CRF exhibit increased anxiety-like behavior [18]. Conversely, CRF1receptor knockout mice have reduced anxiety [17]. Injection of CRF antagonists or CRF1receptor antisense oligonucleotide into the amygdala reduces stress-induced anxiety-like behavior [19,20]. These results collectively show that CRF plays a key role in the regulation of anxiety-like behavior particularly in the amygdala. Therefore understanding the molecular mechanism of the regulation of CRF expression in the amygdala is important. In the present study, using behavioral, pharmacological, and biochemical approaches with knock-in mice in which the Tyr-1472 of GluN2B is mutated to phenylalanine (GluN2B-YF), we have identified Tyr-1472 phosphorylation as a regulator of CRF mRNA expression and anxiety-like behavior. == Results == == Enhanced anxiety-like behavior of GluN2B-YF mice ==.