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Transgenic up-regulation of alpha-CaMKII in forebrain leads to increased anxiety-like behaviors and aggression

DOI: 10.1186/1756-6606-2-6

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Abstract:

We generated transgenic mice overexpressing alpha-CaMKII in the forebrain under the control of the alpha-CaMKII promoter. In contrast to alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in anxiety-like behaviors in open field, elevated zero maze, light-dark transition and social interaction tests, and a decrease in locomotor activity in their home cages and novel environments; these phenotypes were the opposite to those observed in alpha-CaMKII (+/-) heterozygous knockout mice. In addition, similarly with alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in aggression. However, in contrast to the increase in defensive aggression observed in alpha-CaMKII (+/-) heterozygous knockout mice, alpha-CaMKII overexpressing mice display an increase in offensive aggression.Up-regulation of alpha-CaMKII expression in the forebrain leads to an increase in anxiety-like behaviors and offensive aggression. From the comparisons with previous findings, we suggest that the expression levels of alpha-CaMKII are associated with the state of emotion; the expression level of alpha-CaMKII positively correlates with the anxiety state and strongly affects aggressive behavior.Alpha-CaMKII is a Ser/Thr protein kinase that is abundantly expressed in the forebrain [1-5]. In response to an increase in the intracellular concentration of Ca2+, alpha-CaMKII is activated through the binding of Ca2+/calmodulin (CaM), and then phosphorylates target proteins to activate or inactivate these proteins [1-5]. Furthermore, the prolonged activation of alpha-CaMKII by Ca2+/CaM results in the intramolecular autophosphorylation of Thr residues such as T286, T305, and T306 [1-5]. Autophosphorylation of T286 leads to a decrease in the dissociation of bound Ca2+/CaM and continuous partial activation even after the dissociation of Ca2+/CaM, thereby prolonging its activation. Thus, a transient increase in intracellula

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