Possible involvement of DNA methylation in hippocampal synaptophysin gene expression during postnatal development of...

Synaptophysin (Syp) is an integral membrane protein of synaptic vesicles, and is ubiquitously expressed in neurons throughout the brain. As Syp expression is correlated with synaptogenesis during development of the central nervous system, the expression of Syp is considered to be a critical aspect of neuronal maturation and circuit formation. However, little information is available concerning the regulatory mechanisms of Syp gene expression during postnatal development of the brain. In the present study, we investigated changes in Syp mRNA in the hippocampus of mice during postnatal development, and examined the gene regulation mechanisms, focusing on DNA methylation. We found that hippocampal Syp expression involving both mRNA and protein levels increased during the first two weeks of life, and that this increase was accompanied by a transition from hypermethylation to hypomethylation at the CpG sites of the Syp gene upstream region. In addition, DNA demethylating agent 5-Aza-2'-deoxycytidine (5-aza-dC) de-repressed Syp gene expression both in vitro in Neuro-2a mouse neuronal cells and in vivo in the hippocampus of early postnatal mice. Furthermore, the methylation levels at upstream region of Syp gene in the hippocampus of developing mice was decreased by intraperitoneal injection of 5-aza-dC. These results suggest that Syp gene regulation, at least during postnatal brain development, could be mediated by DNA methylation. Our findings promote understanding of the molecular basis of synaptogenesis during postnatal brain development, and provide novel insight into therapeutic aspects of neurodevelopmental disorders involving synaptic dysfunction.