Melatonin Stimulates Dendrite Formation and Complexity in the Hilar Zone of the Rat Hippocampus: Participation of the Ca++/Calmodulin Complex

Abstract

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.

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“…In addition to its chronobiotic effect, melatonin participates in the modulation of neuronal functions, neurodevelopment at early and late stages (Kong et al , ; Chen et al , ) and affects brain structures underlying sleep regulation (Ochoa‐Sanchez et al, ), drug‐related learning (Wang et al, ; Savaskan et al, ) and reward (Hutchinson et al, ; Clough et al, ). MT receptors mediate the melatonin‐induced increase in dendrite length, thickness and complexity of hippocampal neurons, as these effects were partially blocked by luzindole (Dominguez‐Alonso et al, ). Similarly, melatonin‐induced differentiation and maturation of adult neural stem cells were almost abolished in the presence of luzindole (de la Fuente Revenga et al, ).…”

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“…In this regard, melatonin also enhances neurite enlargement by antagonizing the Ca 2+ ‐calmodulin (CaM)‐dependent microtubule depolymerization . Recently, it was demonstrated that melatonin induces the dendritogenesis process in the hilar zone of the hippocampus through CaM translocation to the soluble fraction and CaM‐kinase II stimulation, indicating that it plays a key role in neuronal development and differentiation in the adult brain . Also, in cultured embryonic hippocampal neurons, melatonin stimulates axonal formation through MT2 receptors and activation of MT1 receptor has been implicated in neurite formation at earlier stages …”

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