Tonic Control of Secretory Acid Sphingomyelinase Over Ventral Hippocampal Synaptic Transmission and Neuron Excitability.

Chih-Hung Lin,Fang Zheng,Christian Alzheimer,Johannes Kornhuber

doi:10.3389/fncel.2021.660561

Abstract

The acid sphingomyelinase (ASM) converts sphingomyelin into ceramide. Recent work has advanced the ASM/ceramide system as a major player in the pathogenesis of major depressive disorder (MDD). Indeed, ASM activity is enhanced in MDD patients and antidepressant drugs like fluoxetine act as functional inhibitors of ASM. Here, we employed the specific ASM inhibitor ARC39 to explore the acute effects of the enzyme on hippocampal synaptic transmission and cell excitability in adult mouse brain slice preparations. In both field potential and whole-cell recordings, ARC39 (1–3 μM) enhanced excitatory synaptic input onto ventral hippocampal CA1 pyramidal cells. The specificity of drug action was demonstrated by its lacking effect in slices from ASM knockout mice. In control condition, ARC39 strongly reduced firing in most CA1 pyramidal cells, together with membrane hyperpolarization. Such pronounced inhibitory action of ARC39 on soma excitability was largely reversed when GABAA receptors were blocked. The idea that ARC39 recruits GABAergic inhibition to dampen cell excitability was further reinforced by the drug’s ability to enhance the inhibitory synaptic drive onto pyramidal cells. In pyramidal cells that were pharmacologically isolated from synaptic input, the overall effect of ARC39 on cell firing was inhibitory, but some neurons displayed a biphasic response with a transient increase in firing, suggesting that ARC39 might alter intrinsic firing properties in a cell-specific fashion. Because ARC39 is charged at physiological pH and exerted all its effects within minutes of application, we propose that the neurophysiological actions reported here are due to the inhibition of secretory rather than lysosomal ASM. In summary, the ASM inhibitor ARC39 reveals a tonic control of the enzyme over ventral hippocampal excitability, which involves the intrinsic excitability of CA1 pyramidal cells as well as their excitatory and inhibitory synaptic inputs.

Highlights

Acid sphingomyelinase (ASM) is a phosphodiesterase, which hydrolyzes the membrane constituent sphingomyelin to ceramide and phosphorylcholine
Because ARC39 is charged at physiological pH and exerted all its effects within minutes of application, we propose that the neurophysiological actions reported here are due to the inhibition of secretory rather than lysosomal ASM
To rule out that the rapid augmentation of field excitatory postsynaptic potential (fEPSP) was due to drug effects other than inhibition of ASM, we repeated the experiment in brain slices prepared from ASM knockout mice (ASM-KO)

Summary

Introduction

Acid sphingomyelinase (ASM) is a phosphodiesterase, which hydrolyzes the membrane constituent sphingomyelin to ceramide and phosphorylcholine. The other form, called secretory ASM (S-ASM), is endowed with a complex N-glycosylation pattern, which results in the sorting of the enzyme in a constitutive secretory pathway leading to its release into the extracellular space (Kornhuber et al, 2015). It is worth noting that, under conditions of cellular stress and concomitant elevations in intracellular Ca2+, lysosomes might fuse with the cell membrane and release ASM, representing a second pathway through which the enzyme might reach the extracellular space (Kornhuber et al, 2015)

Methods

Results

Conclusion