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2018 ; 9
(8
): 795
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ZDHHC8 critically regulates seizure susceptibility in epilepsy
#MMPMID30038264
Yang Q
; Zheng F
; Hu Y
; Yang Y
; Li Y
; Chen G
; Wang W
; He M
; Zhou R
; Ma Y
; Xu D
; Tian X
; Gao X
; Wang Q
; Wang X
Cell Death Dis
2018[Jul]; 9
(8
): 795
PMID30038264
show ga
Epilepsy is one of the most prevalent and drug-refractory neurological disorders.
Zinc finger DHHC-type containing 8 (ZDHHC8) is a putative palmitoyltransferase
that is highly expressed in the brain. However, the impact of ZDHHC8 on seizures
remains unclear. We aimed to explore the association of ZDHHC8 with epilepsy and
investigate its in epileptogenesis in in vivo and in vitro models through
behavioral, electrophysiological, and pathological studies. We used kainic acid-
and pilocarpine-induced C57BL/6 mice and magnesium-free-induced pyramidal neurons
as experimental epileptic models in this study. We first found increased ZDHHC8
expression in the brains of temporal lobe epilepsy (TLE) patients, similar to
that observed in chronic epileptic mice, strongly suggesting that ZDHHC8 is
correlated with human epilepsy. In the in vitro seizure models, knocking down
ZDHHC8 using recombinant adeno-associated virus (rAAV) delayed seizure
precipitation and decreased chronic spontaneous recurrent seizures (SRSs) and
epileptiform-like discharges, while ZDHHC8 overexpression had the opposite
effect. ZDHHC8 levels were consistent with seizure susceptibility in induced mice
with SRSs. In an in vitro magnesium-free model, neuronal hyperexcitability and
hypersynchrony were reduced in ZDHHC8-knockdown neurons but were increased in
ZDHHC8-overexpressing neurons. To further explore the potential mechanisms, we
observed that ZDHHC8 had a significant modulatory effect on
2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor-related
excitatory, but not inhibitory, glutamatergic synaptic neurotransmission, further
affecting the inward rectification of AMPA currents in acute hippocampal slices
in whole-cell recordings. ZDHHC8 facilitated GluA1 trafficking to the neuronal
surface in the hippocampus, as shown by immunoprecipitation and Western blotting.
These results suggest that ZDHHC8 may promote the generation and propagation of
seizures in humans and that knocking down ZDHHC8 might produce anti-epileptogenic
effects in drug-resistant epilepsy. Our study provides evidence that may
facilitate the development of an alternative approach for the treatment of
epilepsy by modulating AMPA/GluA1-mediated neurotransmission.
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