Although conditioned inhibition of fear (or learned safety) is a learning process critical for preventing chronic stress, a predisposing factor for depression and other psychopathologies, little is known about its functional purposes or molecular mechanisms. To obtain better insight into learned safety, we investigated its behavioral and molecular characteristics and found that it acts as a behavioral antidepressant in two animal models. Learned safety promotes the survival of newborn cells in the dentate gyrus of the hippocampus, while its antidepressant effect is abolished in mice with ablated hippocampal neurogenesis. Learned safety also increases the expression of BDNF in the hippocampus and leads to downregulation of genes involved in the dopaminergic and neuropeptidergic but not the serotonergic system in the basolateral amygdala. These data suggest that learned safety is an animal model of a behavioral antidepressant that shares some neuronal hallmarks of pharmacological antidepressants but is mediated by different molecular pathways.

R.M.Weseloh and L.A.Pardo contributed equally to this workA short C-terminal domain is required for correct tetrameric assembly in some potassium channels. Here, we show that this domain forms a coiled coil that determines not only the stability but also the selectivity of the multimerization. Synthetic peptides comprising the sequence of this domain in Eag1 and other channels are able to form highly stable tetrameric coiled coils and display selective heteromultimeric interactions. We show that loss of function caused by disruption of this domain in Herg1 can be rescued by introducing the equivalent domain from Eag1, and that this chimeric protein can form heteromultimers with Eag1 while wild-type Erg1 cannot. Additionally, a short endoplasmic reticulum retention sequence closely preceding the coiled coil plays a crucial role for surface expression. Both domains appear to co-operate to form fully functional channels on the cell surface and are a frequent ®nding in ion channels. Many pathological phenotypes may be attributed to mutations affecting one or both domains.

Substantial experimental evidence indicates a major role for the circadian system in mood disorders. Additionally, proinflammatory cytokines have been proposed to be involved in the pathogenesis of depression. However, the molecular elements determining the functional interplay between these two systems in depression have not been described as yet. Here we investigate whether long-term light deprivation in the constant darkness (DD) paradigm affects depression-like behavior in mice and concomitantly modulates the levels of proinflammatory cytokines. We find that after 4 weeks of DD, mice display depression-like behavior, which is paralleled by reduced hippocampal cell proliferation. This chronobiologically induced depressive state is associated with elevated levels of plasma IL-6 (interleukin-6) and IL-6 and Il1-R1 (interleukin 1 receptor, type I) protein levels in the hippocampus and also alters hippocampal protein levels of the clock genes per2 and npas2. Using pharmacological blockers of the NF-κB pathway, we provide evidence that the effects of DD on depression-like behavior, on hippocampal cell proliferation, on altered expressional levels of brain and plasma IL-6, and on the modulation of clock gene expression are mediated through NF-κB signaling. Moreover, NF-κB activity is enhanced in hippocampal tissue of DD mice. Mice with a deletion of IL-6, one of the target genes of NF-κB, are resistant to DD-induced depression-like behavior, which suggests a pivotal role for this cytokine in the constant darkness mouse model of depression. We here first describe some of the molecular elements bridging chronobiological and inflammatory processes in the constant darkness mouse model of depression.

Depression, among other mood disorders, represents one of the most common health problems worldwide, with steadily increasing incidence and major socio-economic consequences. However, since the knowledge about the underlying pathophysiological principles is still very scanty, depression and other mood disorders are currently diagnosed solely on clinical grounds. Currently used treatment modalities would therefore benefit enormously from the development of alternative therapeutic interventions. The implementation of proper animal models is a prerequisite for increasing the understanding of the neurobiological basis of mood disorders and is paving the way for the discovery of novel therapeutic targets. In the past thirty years, since the seminal description of the Forced Swim Test as a system to probe antidepressant activity in rodents, the use of animals to model depression and antidepressant activity has come a long way. In this review we describe some of the most commonly used strategies, ranging from screening procedures, such as the Forced Swim Test and the Tail Suspension Test and animal models, such as those based upon chronic stress procedures, to genetic approaches. Finally we also discuss some of the inherent limitations and caveats that need to be considered when using animals as models for mental disorders in basic research.

Ether à go-go (Eag; KV10.1) voltage-gated K+ channels have been detected in cancer cell lines of diverse origin and shown to influence their rate of proliferation. The tricyclic antidepressant imipramine and the antihistamine astemizole inhibit the current through Eag1 channels and reduce the proliferation of cancer cells. Here we describe the mechanism by which both drugs block human Eag1 (hEag1) channels. Even if both drugs differ in their affinity for hEag1 channels (IC50s are ∼2 μM for imipramine and ∼200 nM for astemizole) and in their blocking kinetics, both drugs permeate the membrane and inhibit the hEag1 current by selectively binding to open channels. Furthermore, both drugs are weak bases and the IC50s depend on both internal an external pH, suggesting that both substances cross the membrane in their uncharged form and act from inside the cell in their charged forms. Accordingly, the block by imipramine is voltage dependent and antagonized by intracellular TEA, consistent with imipramine binding in its charged form to a site located close to the inner end of the selectivity filter. Using inside- and outside-out patch recordings, we found that a permanently charged, quaternary derivative of imipramine (N-methyl-imipramine) only blocks channels from the intracellular side of the membrane. In contrast, the block by astemizole is voltage independent. However, as astemizole competes with imipramine and intracellular TEA for binding to the channel, it is proposed to interact with an overlapping intracellular binding site. The significance of these findings, in the context of structure–function of channels of the eag family is discussed.