An antidepressant behaviour in mice carrying a gene-specific InsP3R1, InsP3R2 and InsP3R3 protein knockdown

Abstract

a b s t r a c tEvidence has accumulated for the involvement of Ca 2þ in the pathophysiology of mood disorders.Elevations in both resting and stimulated intracellular Ca 2þ levels in patients with affective disorders have been reported. The role of inositol-1,4,5-trisphosphate receptors (InsP3Rs), which allow mobilization of intracellular Ca 2þ stores, was, then, investigated in the mouse forced swimming test. InsP3Rantagonists (heparin, xestospongin C) as well as an inositol monophosphatase inhibitor (LiCl) showed an antidepressant activity of intensity comparable to clinically used antidepressants. InsP3Rl, InsP3R2 and InsP3R3 knockdown mice were obtained to investigate the role of InsP3R isoforms. We generated mice carrying a cerebral knockdown of InsP3Rl, InsP3R2 and InsP3R3 proteins by administering antisense oligonucleotides complementary to the sequence of InsP3Rl, InsP3R2 and InsP3R3. These antisensetreated mice showed a specific InsP3R protein level reduction in the mouse cerebral cortex and hippocampus, demonstrated by immunoblotting, immunoprecipitation and immunocytochemistry experiments. Knockdown mice for each InsP3R isoforms showed an antidepressant behaviour and the induced phenotype was reversible disappearing 7 days after the end of the treatment. The absence of impairment of locomotor activity and spontaneous mobility in InsP3R knockdown mice was revealed. These results indicate the involvement of the InsP3R-mediated pathway in the modulation of depressive conditions and may be useful for the development of new therapeutical strategies for the treatment of mood disorders.

Increased Signaling via Adenosine A1 Receptors, Sleep Deprivation, Imipramine, and Ketamine Inhibit Depressive-like Behavior via Induction of Homer1a

“…The long homer scaffolds are bridging metabotropic glutamate receptors with many proteins involved in Ca 2+ signaling (Fagni et al, 2000; Jardin et al, 2013), which have been implicated in the pathophysiology of mood disorders (Galeotti et al, 2008a, 2008b). The short homer1a is lacking the carboxyl-terminal domain and is considered as a dominant- negative regulator of these interactions by disrupting homer clusters by competitive binding to target proteins (Kammermeier and Worley, 2007; Shiraishi-Yamaguchi and Furuichi, 2007).…”

L‐type calcium channels and psychiatric disorders: A brief review

“…In fact, lithium has been shown to indirectly inhibit the inositol-1,4,5-triphosphate receptor (InsP3R) functioning [Schlecker et al, 2006] that plays a fundamental role in calcium release from intracellular stores [Foskett et al, 2007]. Galeotti et al [2008] recently demonstrated that blocking InsP3Rs through pharmacologic or protein knockdown leads to an antidepressant phenotype in mice similar to the effect of antidepressant drugs. Specifically, antidepressant behavior was achieved by administering lithium chloride which presumably acted through the inhibition of inositol monophosphatase and caused phosphoinositol lipid turnover [Phiel and Klein, 2001].…”

“…Specifically, antidepressant behavior was achieved by administering lithium chloride which presumably acted through the inhibition of inositol monophosphatase and caused phosphoinositol lipid turnover [Phiel and Klein, 2001]. As the authors underscored in their article [Galeotti et al, 2008], electroconvulsive therapy (ECT) is one of the most effective treatments for depression and it rapidly reduces the expression of InsP3R in rat brains as well [Kim et al, 2001]. Interestingly, nicardipine, a calcium-channel blocker, was found to enhance the antidepressant action of ECT in 26 patients affected by major depression [Dubovsky et al, 2001].…”

Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders

“…In animal models of depression, inositol trisphosphate receptor inhibitors and other compounds that regulate mitochondrial Ca 2+ influx produced behavioral effects similar to those produced by antidepressants, lithium, and ketamine. 160,161 Additionally, nifedipine and nimodipine have produced promising results in treating and stabilizing mood in both animal Figure 2 Mitochondria are commonly known for their important role in ATP synthesis through the electron transport chain. However, mitochondria also operate in different control systems, such as ROS metabolism and Ca +2 levels, to ensure cellular homeostasis.…”