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

Shunsuke Hasegawa,Shoichi Masushige,Ryouta Maeda,Kenichi Kato,Takahiro Furuichi,Takahisa Miyao,Kengo Endoh,Taro Yoshida,Yasushi Kajii,Megumi Sado,Satoshi Kida,Ryosuke Suzuki,Aya Kitamoto,Seiichi Homma

doi:10.1186/1756-6606-2-6

Shunsuke Hasegawa, Shoichi Masushige + Show 12 more

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https://doi.org/10.1186/1756-6606-2-6

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Abstract

BackgroundPrevious studies have demonstrated essential roles for alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) in learning, memory and long-term potentiation (LTP). However, previous studies have also shown that alpha-CaMKII (+/-) heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important not only for learning and memory but also for emotional behaviors. In this study, to understand the roles of alpha-CaMKII in emotional behavior, we generated transgenic mice overexpressing alpha-CaMKII in the forebrain and analyzed their behavioral phenotypes.ResultsWe 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.ConclusionUp-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.

Highlights

Previous studies have demonstrated essential roles for alpha-calcium/calmodulindependent protein kinase II in learning, memory and long-term potentiation (LTP)
Generation of alpha-CaMKII overexpressing mice To investigate the role of alpha-CaMKII in emotional behavior, we generated transgenic mice overexpressing wild-type alpha-CaMKII in the forebrain using the alphaCaMKII promoter [12,13,14,18,19]
Quantitative immunoblotting with antibodies recognizing alpha-CaMKII revealed 2–2.5 fold higher expression of alpha-CaMKII in the hippocampus and cortex of transgenic mice compared with WT littermates (HP, F1,12 = 5.513, P = 0.0368; CO, F1,12 = 6.382, P = 0.0266; Figure 1C)

Summary

Introduction

Previous studies have demonstrated essential roles for alpha-calcium/calmodulindependent protein kinase II (alpha-CaMKII) in learning, memory and long-term potentiation (LTP). Previous studies have shown that alpha-CaMKII (+/-) heterozygous knockout mice display a dramatic decrease in anxiety-like and fearful behaviors, and an increase in defensive aggression. These findings indicated that alpha-CaMKII is important for learning and memory and for emotional behaviors. Mice with a Thr286 to Ala (T286A) point mutation leading to a lack of the autonomous activity of this kinase have shown severe impairments of spatial learning [9] These findings indicate that alpha-CaMKII is an essential molecule involved in learning and memory. Transgenic mice overexpressing wild-type or a constitutively active mutant (T286D) of alpha-CaMKII in the forebrain showed deficits in learning/memory [1115]

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