Sphingolipids regulate neuromuscular synapse structure and function in Drosophila

Abstract

Sphingolipids are found in abundance at synapses and have been implicated in regulation of synapse structure, function, and degeneration. Their precise role in these processes, however, remains obscure. Serine Palmitoyl‐transferase (SPT) is the first enzymatic step for synthesis of sphingolipids. Analysis of the Drosophila larval neuromuscular junction (NMJ) revealed mutations in the SPT enzyme subunit, lace/SPTLC2 resulted in deficits in synaptic structure and function. Although NMJ length is normal in lace mutants, the number of boutons per NMJ is reduced to ∼50% of the wild type number. Synaptic boutons in lace mutants are much larger but show little perturbation to the general ultrastructure. Electrophysiological analysis of lace mutant synapses revealed strong synaptic transmission coupled with predominance of depression over facilitation. The structural and functional phenotypes of lace mirrored aspects of Basigin (Bsg), a small Ig‐domain adhesion molecule also known to regulate synaptic structure and function. Mutant combinations of lace and Bsg generated large synaptic boutons, while lace mutants showed abnormal accumulation of Bsg at synapses, suggesting that Bsg requires sphingolipid to regulate structure of the synapse. In support of this, we found Bsg to be enriched in lipid rafts. Our data points to a role for sphingolipids in the regulation and fine‐tuning of synaptic structure and function while sphingolipid regulation of synaptic structure may be mediated via the activity of Bsg.

Lipid metabolism in astrocytic structure and function

“…Antibody-mediated ganglioside clustering can activate signalling pathways that inhibit neurite outgrowth [88,89]. Sphingolipids are heavily enriched at synapses, and production is required for regulation of synapse structure and output [90]. It is currently hypothesised that normal production of gangliosides by astrocytes also enhances neurite outgrowth, regulates neuronal inflammation and stabilises neuron-glia interactions [83].…”

Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila

“…The Drosophila third instar larval neuromuscular junction (NMJ) is a well characterised model synapse with [15,33,34]. As a result, it has become a well-established tool for the study of neuronal structure and function in Drosophila models of neurodegeneration [33][34][35][36]. Morphological analysis of the NMJ at muscle 6/7 hemi-segment A3 revealed pan-neuronal expression AP1000 results in a significant reduction in NMJ length, (p < .001) coupled with a reduction in the number of bruchpilot/nc82 positive active zones (p < .05), when compared to wild type (Fig.…”

Extending a Hodgkin-Huxley Model for Larval Drosophila Muscle Excitability via Particle Swarm Fitting

“…Figure 2(A) shows an intracellular microelectrode recording obtained from a filleted preparation of a 3rd instar larval Drosophila, which clearly shows a train of spikes: regenerative depolarising action potentials. Larval fillet preparations and intracellular recordings were made using standard techniques [27]. The preparation was bathed in a normal HL3.1 physiological saline (containing 1.5 mM Ca 2+ ; 4 mM M g 2+ ) without any ion channel blockers.…”