Regional upregulation of hippocampal melatonin MT2 receptors by valproic acid: Therapeutic implications for Alzheimer's disease

We have reported that clinically relevant concentrations of valproic acid (VPA) upregulate the G protein-coupled melatonin MT1 receptor in rat C6 glioma cells, and both MT1 and MT2 receptors in the rat hippocampus. The melatonin MT2 receptor is relatively enriched in the hippocampus, where it is thought to be involved in modulating synaptic plasticity and cognitive function. Importantly, a significant decrease in MT2 expression has been observed in the hippocampus of Alzheimer's patients. Therefore, we examined whether the global upregulation of this receptor (and also the MT1) by VPA, observed in earlier RT-PCR and real time PCR studies, could be localized to more discrete hippocampal regions, which are involved in cognitive function. In situ hybridization of rat brain slices, following chronic VPA treatment (3 mg/mL or 4 mg/mL in drinking water), revealed a significant upregulation of the MT2 receptor mRNA in the CA1, CA2, CA3 and dentate gyrus (DG) regions of the rat hippocampus. In contrast, the MT1 receptor was not detected in the hippocampus by in situ hybridization. The significant induction of melatonin MT2 receptor expression by VPA in hippocampal regions involved in learning, memory and/or neural stem cell proliferation, suggests that a combinatorial therapeutic strategy involving VPA together with melatonin or other MT2 agonists, would be beneficial in neurodegenerative disorders such as Alzheimer's disease.