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, 36 (3), 2347-59

Serotonin of Mast Cell Origin Contributes to Hippocampal Function

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Serotonin of Mast Cell Origin Contributes to Hippocampal Function

Katherine M Nautiyal et al. Eur J Neurosci.

Abstract

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.

Conflict of interest statement

Any Conflict of Interest: No conflict of interest

Figures

Figure 1
Figure 1. Mast cell location in the brain
(A) Sagittal view of the location of mast cells in PN1 and adult mice are shown. Each dot represents one mast cell (blue) in relation to the hippocampus (red). Mast cells are located in the parenchyma of the hippocampus as well as the leptomeninges adjacent to the hippocampus. (B) Coronal view of adult brain depicts the intracranial location of mast cells from bregma-2.30 to -3.40mm with each dot representing one mast cell. (C) The total number of intracranial mast cells (x±sem) and (D) the number of mast cells within or near the hippocampal formation is shown throughout development (E) The % of the total population that these mast cells comprise (within and near hippocampus/ total brain mast cells × 100) is shown.
Figure 2
Figure 2. Mast cells in the brain at low (upper panels) and high (lower panels) magnification
(A) Mast cells are stained with toluidine blue (left) and avidin (right). Arrowheads indicate representative double labeled mast cells. (B) Photomicrographs of toluidine blue stained mast cells located within the hippocampal parenchyma (i, iv) or meninges (ii, iii, v, vi) near the hippocampus. Scale bars,100 μm all upper panels; 5 μm for A bottom panels and B iv, v; and 60 μm for B vi.
Figure 3
Figure 3. Effects of mast cell degranulation on hippocampal serotonin content in mast cell deficient Wsh/Wsh and Wsh/+ mice
The contribution of mast cells to serotonin content in the rostral (blue) and caudal (red) hippocampus is shown following stimulation with (A) HBSS vehicle or (B) C48/80. There were no significant differences between genotypes in either rostral or caudal hippocampus following HBSS vehicle application or in rostral hippocampal slices stimulated with C48/80. However, in brain slices from Wsh/+ but not Wsh/Wsh mice, there were increases in serotonin in the caudal hippocampus following stimulation with C48/80. *, p<0.05.
Figure 4
Figure 4. Spatial memory in Wsh/+ and Wsh/Wsh mice in radial arm and Morris water mazes
(A) The number of errors in the radial arm maze is shown for training and reversal trials. (B) The percentage of trials in which mice performed a serial search is shown. (C) Escape latency in the Morris water maze is shown over hidden and visible platform trials. (D) Representative swim paths of Wsh/+ and Wsh/Wsh mice during the probe trial are shown. Dashed lines demarcate quadrants and the grey box indicates the location of the platform during training. (E) Percent of time spent in each target and nontarget quadrant of the pool during the probe trial is shown for Wsh/+ and Wsh/Wsh mice. Dashed line indicates chance performance (25%). *, p<0.05; **, p<0.01.
Figure 5
Figure 5. Cell proliferation in dentate gyrus and subventricular zone in Wsh/+ and Wsh/Wsh mice
(A) Representative photomicrographs show BrdU staining in the dentate gyrus (bregma -1.8). (B) The number of BrdU+ cells is shown across the rostral-caudal extent of the dentate gyrus. (C) Histogram shows sum of BrdU+ cells in the dentate gyrus. (D) Representative photomicrographs of BrdU staining in the SVZ are shown. (E) Histogram shows the number of BrdU+ cells in the SVZ. *, p<0.05. scale bars, 100 μm
Figure 6
Figure 6. Immature neurons in dentate gyrus in Wsh/+ and Wsh/Wsh mice
(A) Representative photomicrographs of DCX staining in the dentate gyrus of Wsh/+ and Wsh/Wsh mice are shown. The small white box shows location of high magnification inset; Scale bars, 100 μm for hippocampal photomicrograph, 12 μm for inset. (B) Histogram shows the area of DCX staining in the dentate gyrus. **, p<0.01.
Figure 7
Figure 7. Survival and differentiation of cells in dentate gyrus and olfactory bulb in Wsh/+ and Wsh/Wsh mice
(A) Histogram shows % BrdU+ cells surviving in the dentate gyrus for 28 days. (B) The % surviving BrdU+ cells that were also NeuN+ is shown. (C) Representative photomicrographs of BrdU staining in the olfactory bulb of Wsh/+ and Wsh/Wsh mice are shown. Scale bar, 300 μm. (D) Histogram shows the number of BrdU+ cells in olfactory bulb. *, p<0.05
Figure 8
Figure 8. C-kit receptor staining in Wsh/+ and Wsh/Wsh mice
Ckit receptor (red) staining is seen in the cerebellum (left) and hippocampus (right) in sections labeled with GFAP (green, cerebellum) or DCX (green, hippocampus). There were no differences detected between Wsh/+ (top) and Wsh/Wsh (bottom) mice. Low magnification scale bar=100 μm, high magnification inset scale bar=20μm
Figure 9
Figure 9. SSRI treatment effects on neurogenesis in Wsh/+ and Wsh/Wsh mice
(A) The number of BrdU+ cells and (B) the area of DCX staining are shown in response to saline and SSRI treatment. Different letters above the histogram bars indicate statistically significant differences, p<0.05.

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