Synapse-Specific Defects in Synaptic Transmission in the Cerebellum of W246G Mutant ELOVL4 Rats–a Model of Human SCA34

• DOI: 10.1523/jneurosci.0378-23.2023
• Publication Date: 2023-07-25T17:50:36Z
• Authors: Raghavendra Y. Na...; Megan A. Stiles; David M. Sherry; Martin-Paul Agbaga; Mohiuddin Ahmad
• Keywords: Parallel fiber; Climbing fiber

Elongation of very long fatty acids-4 (ELOVL4) mediates biosynthesis chain-fatty acids (VLC-FA; ≥28 carbons). Various mutations in this enzyme result spinocerebellar ataxia-34 (SCA34). We generated a rat model human SCA34 by knock-in naturally occurring c.736T>G, p.W246G mutation the Elovl4 gene. Our previous analysis homozygous W246G mutant ELOVL4 rats (MUT) revealed early-onset gait disturbance and impaired synaptic transmission plasticity at parallel fiber-Purkinje cell (PF-PC) climbing (CF-PC) synapses. However, underlying mechanisms that caused these defects remained unknown. Here, we report detailed patch-clamp recordings from Purkinje cells identify mechanisms. results show miniature EPSC (mEPSC) frequency is reduced MUT with no change mEPSC amplitude, suggesting presynaptic defect excitatory on cells. also find alterations inhibitory as IPSC (mIPSC) amplitude are increased Paired-pulse ratio PF-PC synapses but CF-PC rats, which along high-frequency stimulation suggest opposite changes release probability two In contrast, exaggerated persistence cerebellum, larger readily releasable pool (RRP) both Furthermore, dendritic spine density Thus, our uncover novel action VLC-FA cerebellar synapses, elucidate dysfunction pathology. SIGNIFICANCE STATEMENT Very (VLC-FA) an understudied class present brain. They critical for brain function their deficiency elongation (ELOVL4), biosynthesis, neurologic diseases including (SCA34), neuroichthyosis, Stargardt-like macular dystrophy. study, investigated identified neurotransmitter region involved motor coordination. These advance understanding regulated describe leads to incoordination SCA34.