Regulation of the effects of antidepressants by sphingomyelin- and ceramide-controlled autophagy

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Our previous studies identified the acid sphingomyelinase (Asm)/ceramide system as target for antidepressants such as amitriptyline and fluoxetine. We demonstrated that amitriptyline and fluoxetine reduce Asm activity in the hippocampus and thereby increase neuronal proliferation, maturation, and survival; and improve behaviour in models of stress-induced depression. Genetic deficiency of Asm abrogates the effects of these antidepressants. Mice overexpressing Asm show constitutive changes associated with mild major depressive disorder (MDD). We showed that amitriptyline and fluoxetine induce autophagy in hippocampal neurons via a slow accumulation of sphingomyelin in lysosomes and Golgi bodies and of ceramide in the endoplasmic reticulum (ER). ER ceramide stimulates phosphatase 2A (PP2A), Ulk, Beclin, PI3K/Vps34, p62 and Lc3B and thereby autophagy and the formation of autophagolysosomes. Direct inhibition of sphingomyelin synthases with D609 results in rapid accumulation of ceramide in the ER, activation of autophagy and rapid reversal of stress-induced MDD. Inhibition of Beclin blocks the antidepressive effects of amitriptyline and D609 and induces cellular and behavioural changes typical of MDD. We will now investigate the hypothesis that antidepressants act by regulating the balance between ceramide in the ER, which induces autophagy and counteracts MDD, and ceramide in lysosomes, which reduces autophagy and thereby induces MDD:1. We will elucidate the role of autophagolysosome formation in the treatment of MDD (models) by using a panel of knock-out mice and transgenic mice. We will determine whether autophagolysosome formation occurs in vivo in the hippocampus, is altered upon induction of MDD, and is corrected by antidepressants; we will also determine whether autophagolysosome formation is required for the biochemical and behavioural effects of antidepressants. Molecular and cellular mechanisms by which autophagy determines the effects of antidepressants will be analyzed. 2. We will determine whether lysosomal ceramide affects autophagosome-lysosome fusion, lysosomal reformation, or both and thereby induces MDD.Ultimately, we aim to develop novel, fast-acting antidepressants by targeting sphingolipids to induce the formation of autophagolysosomes.