In the course of adult hippocampal neurogenesis, the postmitotic maturation and survival phase is associated with dendrite maturation. Melatonin modulates the survival of new neurons with relative specificity. During this phase, the new neurons express microtubule-associated protein doublecortin (DCX). Here, we show that the entire population of cells expressing DCX is increased after 14 days of treatment with melatonin. As melatonin also affects microtubule polymerization which is important for neuritogenesis and dendritogenesis, we studied the consequences of chronic melatonin administration on dendrite maturation of DCX-positive cells. Treatment with melatonin increased the number of DCX-positive immature neurons with more complex dendrites. Sholl analysis revealed that melatonin treatment lead to greater complexity of the dendritic tree. In addition, melatonin increased the total volume of the granular cell layer. Besides its survival-promoting effect, melatonin thus also increases dendritic maturation in adult neurogenesis. This might open the opportunity of using melatonin as an adjuvant in attempts to extrinsically stimulate adult hippocampal neurogenesis in neuropsychiatric disease, dementia or cognitive ageing.

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Neuropsychiatric disorders are characterized by hippocampus decreased volume and loss of dendrite arborizations in the subiculum and prefrontal cortex. These structural changes are associated with diminished memory performance. Hilar neurons of the hippocampus integrate spatial memory and are lost in dementia. They receive information from dentate gyrus neurons through dendrites, while they send axonal tracts to the CA3 region. Dendrites are complex structures of neurons that receive chemical information from presynaptic and postsynaptic terminals. Melatonin, the main product of the pineal gland, has neuroprotective actions through its free radical-scavenging properties and decreases neuronal apoptosis. Recently, we found that melatonin increases dendrite maturation and complexity in new neurons formed in the dentate gyrus of mice. In addition, in N1E-115 cultured cells, the indole stimulates early stages of neurite formation, a process that is known to antecede dendrite formation and maturation. Thus, in this study, we explored whether melatonin stimulates dendrite formation and complexity in the adult rat hippocampus in organotypic slice cultures, which is a model that preserves the hippocampal circuitry and their tridimensional organizations of connectivity. The effects of melatonin were studied in nonpathological conditions and in the absence of harmful agents. The results showed that the indole at nocturnal concentrations reached in the cerebrospinal fluid stimulates dendritogenesis at formation, growth, and maturation stages. Also, data showed that dendrites formed became competent to form presynaptic specializations. Evidence strongly suggests that melatonin may be useful in the treatment of neuropsychiatric diseases to repair the loss of dendrites and re-establish lost synaptic connections.

Melatonin (MEL), the main product synthesized by the pineal gland, stimulates early and late stages of neurodevelopment in the adult brain. MEL increases dendrite length, thickness and complexity in the hilar and mossy neurons of hippocampus. Dendrite formation involves activation of Ca2+/Calmodulin (CaM)-dependent kinase II (CaMKII) by CaM. Previous work showed that MEL increased the synthesis and translocation of CaM, suggesting that MEL activates CaM-dependent enzymes by this pathway. In this work we investigated whether MEL stimulates dendrite formation by CaMKII activation in organotypic cultures from adult rat hippocampus. We found that the CaMKII inhibitor, KN-62, abolished the MEL stimulatory effects on dendritogenesis and that MEL increased the relative amount of CaM in the soluble fraction of hippocampal slices. Also, PKC inhibition abolished dendritogenesis, while luzindole, an antagonist of MEL receptors (MT1/2), partially blocked the effects of MEL. Moreover, autophosphorylation of CaMKII and PKC was increased in presence of MEL, as well as phosphorylation of ERK1/2. Our results indicate that MEL stimulates dendrite formation through CaMKII and the translocation of CaM to the soluble fraction. Dendritogenesis elicited by MEL also required PKC activation, and signaling through MT1/2 receptors was partially involved. Data strongly suggest that MEL could repair the loss of hippocampal dendrites that occur in neuropsychiatric disorders by increasing CaM levels and activation of CaMKII.