Neutral Sphingomyelinase is an Affective Valence-Dependent Regulator of Learning and Memory

Abstract

Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signaling in the brain, but sphingolipid contribution to normal behavioral plasticity is little understood. Here we asked how the sphingolipid rheostat contributes to learning and memory of various dimensions. We investigated the role of these lipids in the mechanisms of two different types of memory, such as appetitively and aversively motivated memory, which are considered to be mediated by different neural mechanisms. We found an association between superior performance in short- and long-term appetitively motivated learning and regionally enhanced neutral sphingomyelinase (NSM) activity. An opposite interaction was observed in an aversively motivated task. A valence-dissociating role of NSM in learning was confirmed in mice with genetically reduced NSM activity. This role may be mediated by the NSM control of N-methyl-d-aspartate receptor subunit expression. In a translational approach, we confirmed a positive association of serum NSM activity with long-term appetitively motivated memory in nonhuman primates and in healthy humans. Altogether, these data suggest a new sphingolipid mechanism of de-novo learning and memory, which is based on NSM activity.

COVID-19 and its clinical severity are associated with alterations of plasma sphingolipids and enzyme activities of sphingomyelinase and ceramidase

“…The activity of sphingolipid enzymes was quantified using fluorescent substrates, BODIPY-FL-C12-Sphingomyelin (D-7711, Invitrogen, Carlsbad, CA, USA/Life Technologies, Grand 15 Island, NY, USA) for S-ASM and NSM (Kalinichenko et al 2021a;Kalinichenko et al 2021b) and NBD-C12-ceramide (Cay10007958-1, Cayman Chemical, via Biomol GmbH, Hamburg, Germany) for neutral ceramidase (Kalinichenko et al 2021c) as described previously (Mühle and Kornhuber 2017). Briefly, the reaction was performed in 96 well polystyrene plates with 58 or 50 pmol fluorescently labelled sphingomyelin or Cer, respectively, in a buffer mix totaling 50 µl in volume.…”

Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects

“…NSM is highly expressed in the brain [ 39 , 40 ]. Mice without NSM function in neurons showed a perturbed Golgi secretory pathway, dysproteostasis and impaired learning and memory [ 41 , 42 ]. In the present study, mice with partially reduced NSM function drank less alcohol, possibly because alcohol reduced their affective advantage, i.e.…”

“…NSM enhances the excitability of hippocampal CA1 neurons [ 46 , 47 ]. Individual differences in NSM activity in this brain region predispose for efficient learning and adaptations in particularly appetitively motivated long-term memory tasks [ 42 , 48 , 49 ]. An enhanced capacity of the DH may serve better stress resistance and reduce depression-like behaviour, and provide resilience during initiation of alcohol use [ 50 ].…”

“…However, compensatory changes in the activities of other enzymes of this pathway, particularly ASM or acid and neutral ceramidases, might also be involved in the observed behavioural endophenotype. These enzymes were recently shown to contribute to drug addiction [ 19 , 32 , 57 ], emotional phenotypes [ 8 , 58 ], and cognitive behaviours in rodents [ 42 , 59 ]. However, NSM is the only enzyme of ceramide synthesis and metabolism shown to mediate bone–brain signalling in the co-morbidity trias of alcohol addiction—depression/anxiety—osteoporosis.…”

Endogenous ceramide phosphoethanolamine modulates circadian rhythm via neural–glial coupling in Drosophila

“…CPES (encoded by CG4585 ) and Drosophila SM synthase-related protein (dSMSr) largely govern CPE biosynthesis in flies, in contrast to SM biosynthesis in the mammalian system predominantly mediated by SM synthase 1 and 2 (SMS1 and SMS2) [ 32–34 ]. Common to both mammalian and Drosophila systems, acid and neutral sphingomyelinases (aSMase and nSMase) mediate the conversion of CPE (or SM) into ceramides based on the pH of the microenvironment [ 35 , 36 ]. A previous study showed that Drosophila cpes mutants exhibited photosensitive epilepsy [ 31 ].…”