Title : Antidepressant - like effect of losartan involves TRKB transactivation from angiotensin receptor type 2 ( AGTR 2 ) and recruitment of FYN Authors :

Renin-angiotensin system (RAS) is commonly associated to peripheral fluid homeostasis and cardiovascular function, but recent evidence has also drawn its functional role in the brain. RAS has been described to regulate physiological and behavioral parameters related to stress response, including depressive symptoms. Apparently, RAS can modulate levels of brain derived neurotrophic factor (BDNF) and TRKB, which are important to neurobiology of depression and antidepressant action. However, interaction between BDNF/TRKB system and RAS in depression has not been investigated before. Accordingly, in the forced swimming test, we observed an antidepressant-like effect of systemic losartan but not with captopril or enalapril treatment. Moreover, infusion of losartan into ventral hippocampus (vHC) and prelimbic prefrontal cortex (PL) mimicked systemic losartan effect, whereas K252a, a blocker of TRK, infused into these brain areas impaired the systemic effect of losartan. PD123319, an antagonist of AT2 receptor (AGTR2), infused into PL but not into vHC, also prevented systemic losartan effect. Cultured cortical cells of rat embryos indicate angiotensin II (ANG2) binding to AGTR2 activates TRKB, possibly by recruiting FYN, a SRC family kinase. The higher levels of AGTR2 in cortical cells were inverted after insult with glutamate, and under this condition an interaction between losartan and ANG2 was achieved. Occurrence of TRKB/AGTR2 heterodimers was also observed, since GFP-tagged AGTR2 co-immunoprecipitated with TRKB. Therefore, antidepressant-like effect of losartan is proposed to occur through a shift of ANG2 towards AGTR2, followed by coupling of TRK/FYN and putative TRKB transactivation. Thus, AGTR1 show therapeutic potential as novel antidepressant drug therapy. 2 . CC-BY 4.0 International license not peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/168708 doi: bioRxiv preprint first posted online Jul. 26, 2017; Diniz et al. AGTR2-TRKB transactivation