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Zinc is a trace element that is essential for a large number of biological and biochemical processes in the body. In the nervous system zinc is packaged into synaptic vesicles by the ZnT3 transporter, and synaptic release of zinc can influence the activity of postsynaptic cells, either directly though its own cognate receptors, or indirectly by modulating activation of receptors for other neurotransmitters. Here, we explore the anatomical and functional aspects of zinc in the circadian system. Melanopsin-containing retinal ganglion cells in the mouse retina were found to colocalize ZnT3, indicating that they can release zinc at their synaptic targets. While the master circadian clock in the hamster suprachiasmatic nucleus (SCN) was found to contain, at best, sparse zincergic input, the intergeniculate leaflet (IGL) was found to have prominent zincergic input. Levels of zinc in these areas were not affected by time of day. Additionally, IGL zinc staining persisted following enucleation, indicating other prominent sources of zinc instead of, or in addition to, the retina. Neither enhancement nor chelation of free zinc at either the SCN or IGL altered circadian responses to phase-shifting light in hamsters. Finally, entrainment, free-running, and circadian responses to light were explored in mice lacking the ZnT3 gene. In every aspect explored, the ZnT3-KO mice were not significantly different from their wildtype counterparts. These findings highlight the presence of zinc in areas critical for circadian functioning but have yet to identify a role for zinc in these areas.HighlightsThe synaptic zinc transporter ZnT3 is found in melanopsin-containing retinal ganglion cells.While zinc input to the hamster SCN was found to be sparse at best, prominent zincergic staining was found throughout the IGL.Zinc levels in the SCN and IGL did not change between the night and day.Neither increasing nor decreasing zinc levels in either the SCN or IGL had an influence on circadian responses to light.Mice lacking the ZnT3 transporter did not differ from wildtype mice on a wide variety of circadian measures.

In the adult mammalian brain, up-regulation of serotonin via the selective serotonin reuptake inhibitor fluoxetine increases hippocampal neurogenesis. However, research assessing the long-term effects of modulating serotonin during the developmental period on hippocampal neurogenesis, is sparse. Here we evaluated hippocampal neurogenesis early (postnatal day 12), and later in life (postnatal day 60), in the offspring of mouse dams that were administered fluoxetine in their drinking water from embryonic day 15 (E15) through postnatal day 12 (P12). Fluoxetine-exposed mice had significantly higher levels of neuronal proliferation at P12, and P60, despite cessation of fluoxetine on P12. These effects were limited to proliferation, as survival of postnatal-born hippocampal neurons was unaltered. Mice exposed to fluoxetine also showed significantly higher levels of cell death, suggesting that homeostatic mechanisms present within the hippocampus may limit integration of adult-born neurons into the existing neuronal network. These findings demonstrate modulation of serotonin during development may be sufficient to induce long-lasting changes in hippocampal neurogenesis.

In certain neurons, zinc ions are stored in synaptic vesicles by a membrane transport protein called zinc transporter 3 (ZnT3). Vesicular zinc can then be released synaptically to modulate a number of targets, potentially including brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB). There is in vitro evidence that zinc can interact directly with the BDNF protein; interact with enzymes that cleave BDNF from its precursor, proBDNF; and exert BDNF-independent effects on TrkB. But the effects of vesicular zinc on BDNF and TrkB in the intact brain are not clear. Studies of mice that lack ZnT3 and, as a result, vesicular zinc have shown abnormalities in BDNF and TrkB levels, but results have been mixed and are therefore difficult to interpret. This discrepancy might be caused, at least in part, by differences in the age and sex of mice used in previous studies. In the present study, we measured BDNF and TrkB protein levels in two brain regions, the hippocampus and neocortex, comparing between wild type and ZnT3 knockout mice of both sexes, and including both young (5-week-old) and mature (12-week old) animals. We found that, regardless of age or sex, levels of BDNF and TrkB (truncated or full-length) did not differ between wild type and ZnT3 knockout mice. There was a sex difference in BDNF expression, however; in both hippocampus and neocortex, BDNF levels increased with age in female mice but not in male mice. And male mice had greater neocortical levels of full-length TrkB than did female mice. We conclude that, at least in naive mice housed under standard laboratory conditions, vesicular zinc is not involved in the processing of BDNF, and elimination of vesicular zinc does not affect BDNF or TrkB levels.

Chronic stress can have deleterious effects on mental health, increasing the risk of developing depression or anxiety. But not all individuals are equally affected by stress; some are susceptible while others are more resilient. Understanding the mechanisms that lead to these differing outcomes has been a focus of considerable research. One unexplored mechanism is vesicular zinc – zinc that is released by neurons as a neuromodulator. We examined how chronic stress, induced by repeated social defeat, affects mice that lack vesicular zinc due to genetic deletion of zinc transporter 3 (ZnT3). These mice, unlike wild type mice, did not become socially avoidant of a novel conspecific, suggesting resilience to stress. However, they showed enhanced sensitivity to the potentiating effect of stress on cued fear memory. Thus, the contribution of vesicular zinc to stress susceptibility is not straightforward. Stress also increased anxiety-like behaviour but produced no deficits in a spatial Y-maze test. We found no evidence that microglial activation or hippocampal neurogenesis accounted for the differences in behavioural outcome. Volumetric analysis revealed that ZnT3 KO mice have larger corpus callosum and parietal cortex volumes, and that corpus callosum volume was decreased by stress in ZnT3 KO, but not wild type, mice. Keywords: Synaptic zinc, SLC30A3, Chronic stress, Depression, Fear memory, Magnetic resonance imaging (MRI)

Depression, anxiety, and stress are common in pregnant women. One of the primary pharmacological treatments for anxiety and depression is the antidepressant fluoxetine (Flx). Maternal stress, depression, and Flx exposure are known to effect neurodevelopment of the offspring, however, their combined effects have been scarcely studied, especially in female offspring. The present study investigated the combined effects of maternal stress during pregnancy and perinatal exposure to Flx on the behaviour of female mice as adults. METHODS: Mouse dams were exposed to either chronic unpredictable stress (embryonic (E) day 7 to E18), or FLX (E15-postnatal day 12), or a combination of stress and FLX or left untreated. At two months of age, the female offspring went through a comprehensive behavioural test battery. RESULTS: Maternal stress led to increased activity and alterations of prepulse inhibition in the adult female offspring. Maternal treatment with Flx had a potentially beneficial effect on spatial memory. The combination of prenatal stress and perinatal Flx exposure did not interact in their effects. These results suggest that gestational Flx exposure may have a limited negative impact on female offspring.