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

  • Sci Rep. 2015 Dec 9;5:17816. doi: 10.1038/srep17816.
Michael S Hildebrand  1 ,  A Marie Phillips  2  3 ,  Saul A Mullen  2 ,  Paul A Adlard  2 ,  Katia Hardies  4  5 ,  John A Damiano  1 ,  Verena Wimmer  2 ,  Susannah T Bellows  1 ,  Jacinta M McMahon  1 ,  Rosemary Burgess  1 ,  Rik Hendrickx  4 ,  Sarah Weckhuysen  4  5 ,  Arvid Suls  4  5 ,  Peter De Jonghe  4  5  6 ,  Ingrid E Scheffer  1  2  7 ,  Steven Petrou  2 ,  Samuel F Berkovic  1 ,  Christopher A Reid  2
Affiliations
  • 1. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia.
  • 2. The Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Parkville 3052, Victoria, Australia.
  • 3. School of Biosciences, University of Melbourne, Parkville 3052, Australia.
  • 4. Neurogenetics Group, Department of Molecular Genetics, VIB, Belgium.
  • 5. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Belgium.
  • 6. Division of Neurology, Antwerp University Hospital, Antwerp, Belgium.
  • 7. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville 3052, Victoria, Australia.
PMID: 26647834 DOI: 10.1038/srep17816
Abstract

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.