Melatonin Influences Structural Plasticity in the Axons of Granule Cells in the Dentate Gyrus of Balb/C Mice

Abstract

Melatonin, the main product synthesized by the pineal gland, acts as a regulator of the generation of new neurons in the dentate gyrus (DG). Newborn neurons buffer the deleterious effects of stress and are involved in learning and memory processes. Furthermore, melatonin, through the regulation of the cytoskeleton, favors dendrite maturation of newborn neurons. Moreover, newborn neurons send their axons via the mossy fiber tract to Cornu Ammonis 3 (CA3) region to form synapses with pyramidal neurons. Thus, axons of newborn cells contribute to the mossy fiber projection and their plasticity correlates with better performance in several behavioral tasks. Thus, in this study, we analyzed the impact of exogenous melatonin (8 mg/kg) administered daily for one- or six-months on the structural plasticity of infrapyramidal- and suprapyramidal mossy fiber projection of granule cells in the DG in male Balb/C mice. We analyzed the mossy fiber projection through the staining of calbindin, that is a calcium-binding protein localized in dendrites and axons. We first found an increase in the number of calbindin-positive cells in the granular cell layer in the DG (11%, 33%) after treatment. Futhermore, we found an increase in the volume of suprapyramidal (>135%, 59%) and infrapyramidal (>128%, 36%) mossy fiber projection of granule neurons in the DG after treatment. We also found an increase in the volume of CA3 region (>146%, 33%) after treatment, suggesting that melatonin modulates the structural plasticity of the mossy fiber projection to establish functional synapses in the hippocampus. Together, the data suggest that, in addition to the previously reported effects of melatonin on the generation of new neurons and its antidepressant like effects, melatonin also modulates the structural plasticity of axons in granule cells in the DG.

Melatonin-Induced Cytoskeleton Reorganization Leads to Inhibition of Melanoma Cancer Cell Proliferation

“…This phenomenon could be related to the stop in the cell cycle, since the melatonin retaining the cells in G2/M for a longer period would cause this increase in the number of mitosis. On the other hand, and in relation to this phenomenon, we study the state of the cellular cytoskeleton, since as previously described by other groups, melatonin acts as a modulator of cytoskeleton proteins, altering the actin microfilaments to a greater extent, although It also acts at the level of microtubules, which are highly related to the mitotic processes of anaphase, telophase and cytokinesis [38,39]. When the levels of these proteins are altered, mitosis can suffer abnormalities that lead to the increment of the growth delay, as in our case.…”

Melatonin Modulates Dendrite Maturation and Complexity in the Dorsal- and Ventral- Dentate Gyrus Concomitantly with Its Antidepressant-Like Effect in Male Balb/C Mice

“…Melatonin is one of the key individual regulators of adult hippocampal neurogenesis, and its effects have been demonstrated at different levels of the neurogenic process including cell proliferation, survival and the generation of new neurons but also on the structural plasticity of axons of granule cells [15][16][17][18][19][20][21][22][23][24]26] Interestingly, new neurons buffer the effects of stress [2,3] and increase evidence have supported the antidepressant-like effect of melatonin in predictive animal models of stress, i.e., [15][16][17]19,[31][32][33][34]. However, the antidepressant-like effect of melatonin is reporting in different studies after the administration of different doses of melatonin ranging from 5 to 10 mg/kg [15][16][17]19,[28][29][30]).…”

“…However, the mechanism that underlay the effects of melatonin on dendrite maturation deserves exploring in an additional complex study, including in vitro precursor cells, which is currently conducting in our group. However, it is important to note that melatonin acts on four key events (proliferation, survival, dendrite maturation and axonal growth) of the adult hippocampal neurogenic process in Balb/C mice [25,26]. Also, melatonin could influence the dentate gyrus microenvironment by increasing the levels of neurotrophins or growth factors.…”

“…Besides, previous studies showed consistent results of melatonin on several events of the neurogenic process in C57Bl/6 mice or CD1 mice (i.e., [15][16][17]24]). Explicitly, melatonin favored cell proliferation, survival, intermediate stages of adult hippocampal neurogenesis during ageing of Balb/C mice [25] and the structural plasticity of mossy fibers in granule cells [26]. Also, melatonin stimulates dendrite maturation of doublecortin (DCX)-associated cells in C57Bl/6 mice [24].…”

“…Interestingly, the pro-neurogenic or anti-depressive like effects of melatonin analyzed in separated studies after the administration of different doses of melatonin ranging from 2.5 to 10 mg/kg, i.e., [15][16][17]19,[21][22][23][24][25][26][27][28][29][30][31][32][33][34]. However, the information related to the capability of melatonin to modulate dendrite maturation and complexity in the dorsal-and ventral-regions of the DG and their relationship with its antidepressant-like effect is not known.…”