Cognitive Loss in Zinc Transporter-3 Knock-Out Mice: A Phenocopy for the Synaptic and Memory Deficits of Alzheimer's Disease?

Zinc transporter-3 (ZnT3) protein controls synaptic vesicular Zn 2+ levels, which is predicted to regulate normal cognitive function. Surprisingly, previous studies found that 6- to 10-week-old ZnT3 knock-out (KO) mice did not show impairment in the Morris water maze. We hypothesized that older ZnT3 KO animals would display a cognitive phenotype. Here, we report that ZnT3 KO mice exhibit age-dependent deficits in learning and memory that are manifest at 6 months but not at 3 months of age. These deficits are associated with significant alterations in key hippocampal proteins involved in learning and memory, as assessed by Western blot. These include decreased levels of the presynaptic protein SNAP25 (−46%; p p p p p p p p p p r 2 = 0.47; p = 0.00019) and particularly in Alzheimer9s disease (AD) (−36%; p 2+ movement leads to cognitive loss, and since extracellular β-amyloid is aggregated by and traps this pool of Zn 2+ , the genetic ablation of ZnT3 may represent a phenocopy for the synaptic and memory deficits of AD.