Limbic NF-KB signalling controls stress-induced anxiety and antidepressant effects independently of the HPA axis

Abstract

Depression and anxiety are among the most prevalent psychiatric diseases. After years of enormous research efforts, a complete picture of the aetiology and mechanisms underlying mood disorders remains unknown. Acute stress has been described as a strong risk factor for triggering the onset of depression and different chronic stress paradigms in rodents develop behavioral endpoints that recapitulate many of the endophenotypes of human depression. Both glucocorticoids and the CRH-CRHR1 system have been proposed to be closely involved in the mechanisms of depression. All approved drugs for depression act primarily upon brains monoamine system. Although the last generation of drugs has improved side effect profiles, they exhibit essentially the same effectiveness rates, and have side effects which may compound compliance. Thus there is an urgent need for new targets for antidepressant drug discovery. In preliminary experiments we performed a protein array screening to underscore changes in the signalome and phosphoproteome in hippocampi of animals chronically treated with antidepressant drugs. Among different new candidate targets we found a strong expression change in several members of the NFKB pathway, especially those involved in the non-canonical NF-KB cascade. To model the in vivo role of the NF-KB pathway in emotional behavior and HPA axis regulation we developed conditional KO (CKO) mice carrying a deletion of the upstream kinase IKKalpha specifically in excitatory neurons of the forebrain. Using these IKKα-CKO mice we analyzed the role of NF-KB on HPA regulation, stress-induced anxiety-like behavior and stress-copying behavior. A strong increase in anxiety-like parameters in CKO mice was observed vs. littermate controls. These effects could not be attributed to alterations in glucocorticoid levels because neither basal nor stress-induced glucocorticoid plasma levels were affected in IKKα-CKO mice. Although NF-KB have been described acting downstream CRH-Receptor 1 and the cross-talk between the glucocorticoid receptor and NF-KB transcription factors is very well documented, the present results discard a role of limbic NF-KB for controlling stress-induced HPA axis response. In addition, the responsiveness to antidepressant drugs has been tested in two classical models: the forced-swim test and the antidepressant-induced neurogenesis. Both parameters were severely affected by chronic antidepressant treatment in IKKα-control mice but not in IKKα-CKO. Based on these results we hypothesized that the NFKB signal transduction pathway plays an important and HPA axis-independent role in antidepressant- and anxiety-related behavior.