Loss of synaptic Zn2+ transporter function increases risk of febrile seizures

2015-12-09

Hildebrand, Michael S

Phillips, A Marie

Mullen, Saul A

Adlard, Paul A

Hardies, Katia

Damiano, John A

Wimmer, Verena

Bellows, Susannah T

McMahon, Jacinta M

Burgess, Rosemary

Hendrickx, Rik

Weckhuysen, Sarah

Suls, Arvid

De Jonghe, Peter

Scheffer, Ingrid E

Petrou, Steven

Berkovic, Samuel F

Reid, Christopher A

Cation Transport Proteins

Seizures, Febrile

Zinc

Journal Article

0000-0002-2311-2174

0000-0003-4580-841X

10.1038/srep17816

Febrile seizures (FS) are the most common seizure syndrome and are potentially a prelude to more severe epilepsy. Although zinc (Zn(2+)) metabolism has previously been implicated in FS, whether or not variation in proteins essential for Zn(2+) homeostasis contributes to susceptibility is unknown. Synaptic Zn(2+) is co-released with glutamate and modulates neuronal excitability. SLC30A3 encodes the zinc transporter 3 (ZNT3), which is primarily responsible for moving Zn(2+) into synaptic vesicles. Here we sequenced SLC30A3 and discovered a rare variant (c.892C > T; p.R298C) enriched in FS populations but absent in population-matched controls. Functional analysis revealed a significant loss-of-function of the mutated protein resulting from a trafficking deficit. Furthermore, mice null for ZnT3 were more sensitive than wild-type to hyperthermia-induced seizures that model FS. Together our data suggest that reduced synaptic Zn(2+) increases the risk of FS and more broadly support the idea that impaired synaptic Zn(2+) homeostasis can contribute to neuronal hyperexcitability.

link

Scientific Reports 2016; 5: 17816

Scientific Reports