Synaptic Zn²⁺ and febrile seizure susceptibility

Zn²⁺ , the second most prevalent trace element in the body, is essential for supporting a wide range of biological functions. While the majority of Zn²⁺ in the brain is protein-bound, a significant proportion of free Zn²⁺ is found co-localized with glutamate in synaptic vesicles and is released in an activity-dependent manner. Clinical studies have shown Zn²⁺ levels are significantly lower in blood and cerebrospinal fluid of children that suffer febrile seizures. Likewise, investigations in multiple animal models demonstrate that low levels of brain Zn²⁺ increase seizure susceptibility. Recent work provides human genetic evidence that disruption of brain Zn²⁺ homeostasis at the level of the synapse is associated with increased seizure susceptibility. In this review, we have explored the clinical, functional and genetic data supporting the view that low synaptic Zn²⁺ increases cellular excitability and febrile seizure susceptibility. Finally, the review focuses on the potential of therapeutic Zn²⁺ supplementation for at risk patients.