Impact of Elovl5 deficiency on cerebellar excitatory synaptic transmission in mice

J Neurosci. 2025 Aug 11:e1529242025. doi: 10.1523/JNEUROSCI.1529-24.2025. Online ahead of print.

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 knockout 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 knockout 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 knockout 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.Significance Statement The gene ELOngase of Very-Long chain fatty acids type 5 (ELOVL5) encodes an enzyme responsible for producing polyunsaturated fatty acids (PUFAs), which are essential to maintain presynaptic membrane flexibility during synaptic transmission. Mutations of ELOVL5 cause Spinocerebellar ataxia type 38 (SCA38, MIM# 615957). This study shows that the complete absence of Elovl5 in mice results in significant alterations in cerebellar excitatory presynaptic mechanisms. Specifically, we found deficits in replenishment of the readily releasable pool of synaptic vesicles at synapses impinging on Purkinje cells, along with disruption of the endocannabinoid-dependent short-term plasticity. These dysfunctions were paralleled by marked changes in lipidic composition of cerebellar tissues, including cerebellar synaptosomes, highlighting the critical role of Elovl5 in cerebellar function.

PMID:40789653 | DOI:10.1523/JNEUROSCI.1529-24.2025