A Reduced Expression of BCL-xL in the Hippocampus Is Accompanied by a Depression-Like Phenotype in Rats

The previously identified ability of the anti-apoptotic protein Bcl-xL to increase expression in the hippocampus in response to stress, which correlated with resistance to stress-induced depression [1], indicates the potential use of this protein as a target for reducing symptoms of depressive disorder. The aim of this work was to evaluate in rats the effect of suppression of Bcl-xL expression in the hippocampus (using a TET-ON system based on lentiviral vectors for doxycycline-controlled transgene expression) on behavior in the forced swim test. The detected decrease in the expression (determined by immunoblotting) of Bcl-xL in the hippocampus and less pronounced in the frontal cortex was accompanied by a clear depressive-like effect, which manifested as a shorter latency before the first episode of freezing and a longer duration of passive behavior. Animals that received joint administration of the vector and doxycycline also showed a significant increase in the expression of brain-derived neurotrophic factor (BDNF) protein in the hippocampus and the relative weight of the adrenal glands, and a decrease in the stress level of corticosterone in the blood plasma compared to groups that received separate administrations of these drugs. Relative adrenal weights showed a significant negative correlation with Bcl-xL expression level in the frontal cortex. In general, gene-directed reduction of Bcl-xL expression in the hippocampus resulted in a depressive-like response in the forced swim test in rats. This behavioral effect was accompanied by a change in the functioning of the adrenal glands, manifested by an increase in the weight of the glands and a decrease in the stress level of corticosterone in the peripheral circulation.