The NFkB alternative pathway is activated by antidepressant drug treatment

LINENBERG, IVANA; VOGL, ANNETTE; GIUSTI, SEBASTIAN; PATRICIO YANKILEVICH; MANOLIS PASPARAKIS; WOLFGANG WURST; FLORIAN HOLSBOER; JAN DEUSSING; DAMIAN REFOJO

Congreso; XXXIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2018

SAN IBRO LARC

Almost 30% of patients suffering from Depression (MDD) remain resistant to the currentmedication and exists pressing need to discover new targets for antidepressant drugdevelopment.Our primary goal is to find new intracellular pathways regulated by antidepressants which couldbe potential targets for drug development. We focused on kinases and phosphoproteins which arewell-known for being drugable targets.As a first step, we carried out a protein array screening to reveal changes in the signalosome andphosphoproteome in the hippocampi of animals chronically treated with paroxetine. We extractedRNA from the same material and performed microarrays in order to compare mRNA and proteinlevels of the candidate molecules. We found strong changes in a number of interesting candidatesincluding 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-αspecifically in excitatory (glutamatergic) neurons of the forebrain. The effects of antidepressantdrugs on different endophenotypes were analyzed on this mouse line at different levels, includingadult neurogenesis, glial activation, depression-like behavior and spine density of principalneurons of the hippocampus. These results point towards a relevant function of the NF-κBpathway on the mechanism of action of antidepressant drugs.