The NFKB alternative pathway is activated by antidepressant drug treatment

LINENBERG, IVANA M.; VOGL, ANNETTE M.; GIUSTI, SEBASTIÁN A.; YANKILEVICH, PATRICIO; PASPARAKIS, MANOLIS; WURST, WOLFGANG; FLORIAN HOLSBOER; JAN M. DEUSSING; REFOJO, DAMIÁN

Córdoba

Congreso; XXXIII Congreso de la Sociedad Argentina de Neurociencias; 2018

Sociedad Argentina de Neurociencias

Almost 30% of patients suffering from Depression (MDD) remain resistant to the current medication and exists pressing need to discover new targets for antidepressant drug development.Our primary goal is to find new intracellular pathways regulated by antidepressants which could be potential targets for drug development. We focused on kinases and phosphoproteins which are well-known for being drugable targets.As a first step, we carried out a protein array screening to reveal changes in the signalosome and phosphoproteome in the hippocampi of animals chronically treated with paroxetine. We extracted RNA from the same material and performed microarrays in order to compare mRNA and protein levels of the candidate molecules. We found strong changes in a number of interesting candidates including several members of the NF-κB pathway.We focused on this pathway and studied its role in emotional behavior and antidepressant action. To do that, we generated a conditional KO mouse line carrying a deletion of the NF-κB kinase IKK-α specifically in excitatory (glutamatergic) neurons of the forebrain. The effects of antidepressant drugs on different endophenotypes were analyzed on this mouse line at different levels, including adult neurogenesis, glial activation, depression-like behavior and spine density of principal neurons of the hippocampus. These results point towards a relevant function of the NF-κB pathway on the mechanism of action of antidepressant drugs.