A reduced expression of Bcl-xL in the hippocampus is accompanied by a depression-like phenotype in rats

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Abstract

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 (Shishkina et al., 2010; Dygalo et al., 2012), 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, manifested by a shorter latency period 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, 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 were significantly negatively correlated with Bcl-xL expression levels in the frontal cortex. Overall, 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.

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About the authors

G. T. Shishkina

The Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences

Author for correspondence.
Email: gtshi@bionet.nsc.ru
Russian Federation, Novosibirsk

D. A. Lanshakov

The Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences

Email: gtshi@bionet.nsc.ru
Russian Federation, Novosibirsk

A. V. Bannova

The Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences

Email: gtshi@bionet.nsc.ru
Russian Federation, Novosibirsk

N. P. Komysheva

The Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences

Email: gtshi@bionet.nsc.ru
Russian Federation, Novosibirsk

N. N. Dygalo

The Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences

Email: gtshi@bionet.nsc.ru
Russian Federation, Novosibirsk

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Supplementary files

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2. Fig. 1. Evaluation of the efficiency of Bcl-xL knockdown by shRNA variants: sh#1 and sh#2, in primary rat fibroblast cells 48 hours after transfection. * - p < 0.05 compared to the control group.

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3. Fig. 2. Bcl-xL (a, b) and BDNF (c, d) protein levels in the hippocampus (a, c) and frontal cortex (b, d) of adult rats that received intrahippocampal injections of lentiviral vector and doxycycline with drinking water separately and together. Dox – doxycycline, Tg ‒ lentiviral vector, Tg+Dox ‒ lentiviral vector followed by doxycycline consumption. M±m values ​​are presented as a percentage relative to the Dox group, taken as 100%; each group included 7–8 animals. Asterisks indicate the differences between the groups: in (a) ‒ p < 0.05 compared to the Dox and Tg groups; in (b) ‒ p < 0.05 compared to the Dox group, with the Tg group at the level of a pronounced tendency ‒ p = 0.0568; in (c) ‒ p < 0.05 compared with both control groups.

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4. Fig. 3. Latent time to first freezing (a) and total duration of freezing (b) in adult rats that received intrahippocampal injections of lentiviral vector and doxycycline with drinking water separately and together in the pretest and test sessions of the forced swim test. Dox – doxycycline, Tg – lentiviral vector, Tg+Dox – lentiviral vector followed by doxycycline consumption; each group included 11–13 animals. The numbers above indicate the groups between which significant differences were found (p < 0.05).

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5. Fig. 4. Relative adrenal weights (a) and stress-related corticosterone levels (b) in the peripheral blood plasma of adult rats that received intrahippocampal injections of lentiviral vector and doxycycline with drinking water separately and together. Dox – doxycycline, Tg ‒ lentiviral vector, Tg+Dox ‒ lentiviral vector followed by doxycycline consumption; each group included 7–8 animals. In (a) ‒ *p < 0.05 compared with Dox groups; in (b) ‒ *p < 0.05 compared with Tg group.

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6. Fig. 5. Stress (30 minutes after forced swimming stress) levels of interleukin-6 in the peripheral blood plasma of adult rats that received intrahippocampal injections of lentiviral vector and doxycycline with drinking water separately and together. Dox – doxycycline, Tg – lentiviral vector, Tg+Dox – lentiviral vector followed by doxycycline intake; each group included 7–8 animals.

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