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 (3mg/mL or 4mg/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.