Lentivirally mediated GSK-3β silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice

Abstract

Inhibition of glycogen synthase kinase-3 (GSK-3) by pharmacological tools can produce antidepressant-like effects in rodents. However, the GSK-3 isoform(s) and brain region(s) involved in regulating these behavioral effects remain elusive. We studied the effects of bilateral intra-hippocampal injections of lentivirus-expressing shRNA targeting GSK-3β on behavioral performance in mice subjected to chronic stress. Pre-injection of lentivirus-expressing GSK-3β shRNA into the hippocampal dentate gyrus significantly decreased immobility time in both forced swim and tail suspension tests, while the locomotor activity of these mice was unchanged. These results suggest that lentiviral GSK-3β shRNA injection induces antidepressant-like effects in chronically stressed mice. Under these conditions, the expression levels of GSK-3β were persistently and markedly reduced in the hippocampus following GSK-3β shRNA injection. To our knowledge, this is the first demonstration that a single injection of lentivirus-expressing GSK-3β shRNA in the hippocampal dentate gyrus of chronically stressed mice has antidepressant-like effects elicited by gene silencing.

Hippocampal GSK3β as a Molecular Link Between Obesity and Depression

“…The involvement of GSK3β signaling in the DG has been thought to play a key role in the physiopathology of depression. For instance, the injection of lentiviral GSK3β shRNA in this region decreases immobility times in the FST and the tail suspension test [23]. However, to our knowledge, this is the first time that the cellular localization of this pathway is established.…”

“…Recent studies have unveiled that the expression and action of GSK3β in the SGZ are essential for its mood-regulating properties [11,23]. In addition, the SGZ of the DG is, along with the subventricular zone and the hypothalamic median eminence, one of the few brain regions where neurogenesis has been reported in the adult brain.…”

Caspase-3 and GFAP as early markers for apoptosis and astrogliosis in shRNA-induced hippocampal cytotoxicity

“…Previous studies have employed shRNA constructs without apparent detrimental effects on cell viability in the hippocampus (Mosser et al, 2015;Omata et al, 2011;Kim et al, 2012). In this study, we applied virus titers within the range chosen by most rAAV-based RNAi studies in the CNS, i.e.…”

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

“…GSK-3 dysfunction has been linked to the pathophysiology of mood disorders, schizophrenia, AD, diabetes, and others (reviewed in Meijer et al, 2004;Huang and Klein, 2006;Jope et al, 2007;Chiu and Chuang, 2010;Li and Jope, 2010). In rodent models, the pharmacological inhibition or gene knockout/knockdown of GSK-3 mimicked lithium's antidepressant and anti-manic effects (KaidanovichBeilin et al, 2004(KaidanovichBeilin et al, , 2009O'Brien et al, 2004;Gould et al, 2004b;Rosa et al, 2008;Jope, 2011;Omata et al, 2011). Despite limited clinical data, some evidence from genetic and postmortem studies supports the role of GSK-3 in mood disorders (for a review, see Jope, 2011).…”