Impact of Elovl5 Deficiency on Cerebellar Excitatory Synaptic Transmission in Mice

Abstract

The neurotransmitter release and the synaptic vesicle cycle require a specific lipidic composition of presynaptic and vesicle membranes. Phospholipids with long-chain acyl groups are necessary to confer to membranes the physical properties necessary for synaptic transmission. Elovl5 is crucial for the elongation of polyunsaturated fatty acids (PUFAs) beyond 18-carbon atoms, and its deletion or mutation causes cerebellar motor deficits in humans and mice. In the mouse cerebellum of both sexes, deletion of Elovl5 increased 18- and 20-carbon atoms PUFAs, decreased long-chain PUFAs, and increased saturated and monounsaturated fatty acids. Electrophysiological recordings in Purkinje cells revealed that basal synaptic transmission was preserved in Elovl5 knock-out mice. However, the recovery from depression of the climbing fiber synapse lacked the fast phase, suggesting a deficit in replenishment of the readily releasable pool of synaptic vesicles. The parallel fiber synapse showed slower replenishment rate of the readily releasable pool at relatively high but physiological frequencies of 50 and 100 Hz. Endocannabinoids contain a long-chain PUFA, and in Purkinje cells, they mediate the synaptically induced suppression of excitation (SSE). In Elovl5 knock-out mice, SSE had a shorter duration, suggesting a role of Elovl5 in this form of synaptic plasticity. Accordingly, we show dramatic change in length and level of unsaturation of lipids in synaptosomes isolated from Elovl5 knock-out mice. These results suggest that the shift in PUFA lipidic species caused by the absence of Elovl5, in the cerebellar cortex, is responsible for specific deficits in neurotransmitter release.