Autophosphorylation of αCaMKII affects social interactions in mice.

The α-Ca2+ /calmodulin-dependent protein kinase II (αCaMKII), a key regulator of the glutamatergic synapse, has been implicated in many psychiatric disorders characterized by social impairments. Here we tested whether autophosphorylation of αCaMKII at threonine 286, which prolongs the activity of the enzyme, affects social behaviors in mice. We observed that autophosphorylation-deficient (αCaMKII-T286A) mutant female mice showed abnormal social behaviors characterized by decreased social preference and interest in conspecifics of the same sex, as compared to their wild-type littermates. Moreover, we developed a mathematical approach to analyze social interactions in group-housed mice in the automated IntelliCages. Using this approach we observed that αCaMKII-T286A mutants show decreased levels of social interactions in a social group, as compared with WT mice. WT mice increased the frequency of close social interactions when learning about the location of the food reward. This phenomenon was absent in the mutants. Overall, our data indicates that autophosphorylation of αCaMKII affects social interactions.

Regulation of cocaine-induced activator protein 1 transcription factors by the extracellular signal-regulated kinase pathway.

Extracellular signal-regulated kinases and activator protein 1 transcription factor have been functionally linked to addiction. It has also been shown that extracellular signal-regulated kinase activation can regulate cocaine-induced expression of c-Fos and FosB, two possible components of activator protein 1. A direct link between extracellular signal-regulated kinases and activator protein 1 activation has, however, remained unexplored. In this study, we investigated the role of extracellular signal-regulated kinases in the regulation of DNA-binding activity and composition of activator protein 1 induced in the mouse caudate putamen by cocaine treatment. We have found that pre-treatment with SL327, a selective inhibitor the extracellular signal-regulated kinase pathway, has no influence on cocaine-induced DNA-binding activity of activator protein 1, when examined one hour after an acute cocaine treatment. This phenomenon results from simultaneous decrease of c-Fos protein level and increases in JunB and deltaFosB protein levels. SL327 pre-treatment, however, reduces the DNA-binding activity of the activator protein 1 complex induced six hours after an acute cocaine treatment as well as one hour after the last of the chronic cocaine injections, a phenomenon that results from the concomitant reduction of all cocaine-induced proteins (c-Fos, FosB, deltaFosB, JunB). In conclusion, we have found that extracellular signal-regulated kinase inhibition may not only interfere with cocaine-induced gene expression and activator protein 1 complex activation, but may also disturb the time-course of gene expression and composition of activator protein 1 complex. Our results support the notion that inhibitors of the extracellular signal-regulated kinase pathway could be valuable tools to obliterate cocaine-induced molecular changes and the development of addiction.

Differential regulation of CaMKII inhibitor beta protein expression after exposure to a novel context and during contextual fear memory formation.

Understanding of the molecular basis of long-term fear memory (fear LTM) formation provides targets in the treatment of emotional disorders. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is one of the key synaptic molecules involved in fear LTM formation. There are two endogenous inhibitor proteins of CaMKII, CaMKII N alpha and N beta, which can regulate CaMKII activity in vitro. However, the physiological role of these endogenous inhibitors is not known. Here, we have investigated whether CaMKII N beta protein expression is regulated after contextual fear conditioning or exposure to a novel context. Using a novel CaMKII N beta-specific antibody, CaMKII N beta expression was analysed in the naïve mouse brain as well as in the amygdala and hippocampus after conditioning and context exposure. We show that in naïve mouse forebrain CaMKII N beta protein is expressed at its highest levels in olfactory bulb, prefrontal and piriform cortices, amygdala and thalamus. The protein is expressed both in dendrites and cell bodies. CaMKII N beta expression is rapidly and transiently up-regulated in the hippocampus after context exposure. In the amygdala, its expression is regulated only by contextual fear conditioning and not by exposure to a novel context. In conclusion, we show that CaMKII N beta expression is differentially regulated by novelty and contextual fear conditioning, providing further insight into molecular basis of fear LTM.