Thesis defense Danielle Mendes Niniz (Donders thesis series 463)

4 November 2020

Promotor: prof. dr. J. Homberg
Co-promotor: dr. J. Grandjean

Unravelling the role of Brain-Derived Neurotrophic Factor in depression
BDNF overexpression in Serotonin Transporter Knockout Rats

Brain-derived neurotrophic factor is one of the most studied proteins playing a pivotal role in neuroplasticity events and vulnerability and resilience to stress-related disorders. Most importantly, BDNF is decreased in depressive patients, and increased after antidepressant treatment. Additionally, BDNF was found to be reduced in a genetic subset of depression susceptible patients carrying the human polymorphism in the serotonin transporter promoter region (5-HTTLPR). The serotonin knockout rat (SERT^-/-) is one of the animal models used to investigate the underlying molecular mechanisms behind the genetic susceptibility to depression in humans. SERT^-/- rats present decreased BDNF levels, especially BDNF exon IV, in the prefrontal cortex (PFC) and ventral hippocampus (vHIP), and display anxiety- and depression-like behavior. To investigate whether upregulating BDNF in the PFC and/or in the vHIP would meliorate the phenotype of SERT^-/- rats, we overexpressed BDNF locally into the rat brain by means of stereotaxic surgery and submitted the animals to behavioral challenges, including the sucrose consumption, the open field, and forced swim tests. Additionally, we measured hypothalamus-pituitary-adrenal (HPA)-axis reactivity. The molecular investigation of BDNF overexpression using a lentivirus vector demonstrated that BDNF is modulated temporally and spatially. Moreover, the upregulation of BDNF IV affected the total BDNF and the expression of BDNF VI, confirming previous studies showing spatial segregation of BDNF transcripts and/or possible BDNF effects in distal areas after overexpression in specific sites. BDNF overexpression in the selected areas – vHIP and PFC – did not modulate the SERT^-/- deficits in all the analyzed behavioral tests. However, the few modifications promoted by BDNF overexpression, together with further studies, should unravel the mechanisms underpinning the BDNF role in the vHIP and PFC of the SERT^-/- rats.

This thesis opens the way to new molecular and behavioral studies that can be employed to further investigate the effects of BDNF overexpression in a rat model presenting both, decreased BDNF expression and anxiety- and depression-like phenotype, features commonly found in clinical studies of patients suffering from mood-related disorders. We hope that collective efforts in the field will ultimately achieve the goal of promoting alternative therapeutic options for those struggling with resistance to current antidepressant options thus contributing to improvement of human mental health.