Serotonin of mast cell origin contributes to hippocampal function

Psychology Department, Columbia University, 406 Schermerhorn Hall, 1190 Amsterdam Ave., New York, NY 10027, USA.
European Journal of Neuroscience (Impact Factor: 3.18). 05/2012; 36(3):2347-59. DOI: 10.1111/j.1460-9568.2012.08138.x
Source: PubMed


In the central nervous system, serotonin, an important neurotransmitter and trophic factor, is synthesized by both mast cells and neurons. Mast cells, like other immune cells, are born in the bone marrow and migrate to many tissues. We show that they are resident in the mouse brain throughout development and adulthood. Measurements based on capillary electrophoresis with native fluorescence detection indicate that a significant contribution of serotonin to the hippocampal milieu is associated with mast cell activation. Compared with their littermates, mast cell-deficient C57BL/6 Kit(W-sh/W-sh) mice have profound deficits in hippocampus-dependent spatial learning and memory and in hippocampal neurogenesis. These deficits are associated with a reduction in cell proliferation and in immature neurons in the dentate gyrus, but not in the subventricular zone - a neurogenic niche lacking mast cells. Chronic treatment with fluoxetine, a selective serotonin reuptake inhibitor, reverses the deficit in hippocampal neurogenesis in mast cell-deficient mice. In summary, the present study demonstrates that mast cells are a source of serotonin, that mast cell-deficient C57BL/6 Kit(W-sh/W-sh) mice have disrupted hippocampus-dependent behavior and neurogenesis, and that elevating serotonin in these mice, by treatment with fluoxetine, reverses these deficits. We conclude that mast cells contribute to behavioral and physiological functions of the hippocampus and note that they play a physiological role in neuroimmune interactions, even in the absence of inflammatory responses.

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    • "N-cadherin or synaptic cell adhesion molecule (SynCAM) (Suzuki et al. 2004; Furuno et al. 2005). Mast cell-derived serotonin contributes to neurogenesis and to the behavioral and physiological function of the hippocampus (Nautiyal et al. 2012). Mast cell proteases, such as tryptase, signal nerves through PARs; PAR2 activation has been implicated in increased intestinal permeability and visceral hypersensitivity in rodents (Déry et al. 1998; Vergnolle et al. 2001; Coelho et al. 2002; Cenac et al. 2003). "
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    ABSTRACT: Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role.
    Acta histochemica et cytochemica official journal of the Japan Society of Histochemistry and Cytochemistry 07/2014; 62(10). DOI:10.1369/0022155414545334 · 1.39 Impact Factor
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    • "KMO inactivation prevents IL-1β inhibition of neurogenesis, suggesting a powerful role for IDO and the TRYCAT pathway in driving inflammation induced decreased neurogenesis. TDO and IDO activation decreases mast cell serotonin production, also important to dentate gyrus neurogenesis, as well as learning and mood [148]. Such data emphasizes the importance of the TRYCATs in mediating depression/somatization associations with degenerative and regenerative processes in PD. "
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    ABSTRACT: Increased depression, somatization, gut inflammation and wider peripheral inflammation are all associated with the early stages of Parkinson's disease (PD). Classically such concurrent conditions have been viewed as "comorbidities", driven by high levels of stress in a still poorly understood and treated disorder. Here we review the data on how oxidative and nitrosative stress in association with immuno-inflammatory responses, drives alteration in tryptophan catabolites, including kynurenine, kynurenic acid and quinolinic acid that drive not only the "comorbidities" of PD but also important processes in the etiology and course of PD per se. The induction of indoleamine 2,3-dioxygenase, leading to the driving of tryptophan into neuroregulatory tryptophan catabolite products and away from serotonin and melatonin production, has significant implications for understanding the role of nicotine, melatonin, and caffeine in regulating PD susceptibility. Tryptophan catabolite pathway activation will also regulate blood-brain barrier permeability, glia and mast cell reactivity as well as wider innate and adaptive immune cell responses, all relevant to the course of PD. As such, the "comorbidities" of PD such as depression, somatization and peripheral inflammatory disorders can all be conceptualized as being an intricate part of the biological underpinnings of both the etiology and course of PD. As a consequence, the data reviewed here has treatment implications; relevant to both the course of PD and in the management of L-DOPA induced dyskinesias.
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    • "Using CE-LIF, the Gillette group (Hatcher et al., 2008) quantitatively measured how 5-HT and related indole metabolites fluctuate with hunger state in well-characterized serotonergic neurons of the feeding motor network of the predatory sea-slug Pleurobranchaea californica. Silver and collaborators (Nautiyal et al., 2012) found that a significant contribution of serotonin to the hippocampal milieu is associated with mast cell activation, which contributes to behavioral and physiological functions of the hippocampus, and later compared the transcriptome and the CE-MS defined metabolome of hippocampi from normal and mast cell deficient mice (see Fig. 3B) (Knolhoff et al., 2013). "
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    ABSTRACT: Modern science is characterized by integration and synergy between research fields. Accordingly, as technological advances allow new and more ambitious quests in scientific inquiry, numerous analytical and engineering techniques have become useful tools in biological research. The focus of this review is on cutting edge technologies that aid direct measurement of bioactive compounds in the nervous system to facilitate fundamental research, diagnostics, and drug discovery. We discuss challenges associated with measurement of cell to cell signaling molecules in the nervous system, and advocate for a decrease of sample volumes to the nanoliter volume regime for improved analysis outcomes. We highlight effective approaches for the collection, separation, and detection of such small-volume samples, present strategies for targeted and discovery-oriented research, and describe the required technology advances that will empower future translational science.Neuropsychopharmacology accepted article preview online, 10 June 2013; doi:10.1038/npp.2013.145.
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