title: Autism phenotypes in ZnT3 null mice: Involvement of zinc dyshomeostasis, MMP-9 activation and BDNF upregulation.
abstract: To investigate the role of synaptic zinc in the ASD pathogenesis, we examined zinc transporter 3 (ZnT3) null mice. At 4-5 weeks of age, male but not female ZnT3 null mice exhibited autistic-like behaviors. Cortical volume and neurite density were significantly greater in male ZnT3 null mice than in WT mice. In male ZnT3 null mice, consistent with enhanced neurotrophic stimuli, the level of BDNF as well as activity of MMP-9 was increased. Consistent with known roles for MMPs in BDNF upregulation, 2.5-week treatment with minocycline, an MMP inhibitor, significantly attenuated BDNF levels as well as megalencephaly and autistic-like behaviors. Although the ZnT3 null state removed synaptic zinc, it rather increased free zinc in the cytosol of brain cells, which appeared to increase MMP-9 activity and BDNF levels. The present results suggest that zinc dyshomeostasis during the critical period of brain development may be a possible contributing mechanism for ASD.
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Min Heui
authors.initials: MH
authors.lastname: Yoo
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Tae-Youn
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Yoon
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Korea.|Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D004789:Enzyme Activation / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000172:deficiency*; D026901:Membrane Transport Proteins; D008817:Mice, Mutant Strains; D010641:Phenotype; D015854:Up-Regulation; D015032:Zinc / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C491177:Slc30a3 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D015032:Zinc