Mast cells modulate maintained neuronal activity in the thalamus in vivo

www.elsevier.com/locate/jneuroim

Journal of Neuroimmuno

Mast cells modulate maintained neuronal activity in the thalamus in vivo

Peter Kovacs a,*, Istvan Hernadi a,b, Marta Wilhelm c

a University of Pecs, Department of Experimental Zoology and Neurobiology, 6 Ifjusag str., H-7624, Pecs, Hungaryb University of Cambridge, Department of Anatomy, Downing Street, Cambridge, CB2 3DY, United Kingdomc University of Pecs, Institute of Physical Education and Sport Sciences, 6 Ifjusag str., H-7624, Pecs, Hungary

Received 22 April 2005; accepted 15 July 2005

Abstract

Single cell unit activity of 187 neurons of 24 rats were analysed to study the possible involvement of intracranial mast cells on modifying

thalamic neuronal activity. Mast cells were activated with microiontophoretical application of compound 48/80. This substance did not

modify the firing rate of cortical or hippocampal neurons (no mast cells are found here), however it caused excitation (70% in females, 11%

in males), or inhibition (7% in females, 33% in males) on thalamic neurons, possibly due to mast cell activation. In consecutive anatomical

evaluation many partially or fully degranulated mast cells were found in the recorded thalamic areas.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Compound 48/80; Iontophoresis; Mast cells

1. Introduction

Mast cells were found in many different species, in a

variety of organs including the central nervous system. In

rats they were located mostly in the thalamic region of the

brain, some in the hypothalamus and almost none in the

hippocampus or in cortical regions (Bugajski et al., 1995).

They are also present in large number in the dura and pia

mater (Rozniecki et al., 1997). Thalamic mast cells are

found in and around blood vessels (Goldschmidt et al.,

1985), and on the neuronal side of the blood–brain barrier

(Dimitriadou et al., 1990; Zhuang et al., 1999). Although the

function of intracranial mast cells is not clearly defined yet,

we know that they are able to synthesize, store and release a

wide range of neurotransmitters and neuromodulators, such

as histamine (Ikarashi and Yuzurihara, 2002), GnRH (Khalil

et al., 2003; Silverman et al., 1994), or monoamines (Silver

et al., 1996) and specific proteases, cytokines (Rozniecki et

al., 1997). The number of the thalamic mast cells is highly

0165-5728/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.jneuroim.2005.07.026

* Corresponding author. Tel.: +36 72503600x4613 or 4816; mobile: +36

702895618; fax: +36 72501517.

E-mail address: [email protected] (P. Kovacs).

dependent on the sex, age or the behavioural state of the

animal (Asarian et al., 2002). In rats their number is higher

in females than in males and more cells were found on the

left side of the brain (Goldschmidt et al., 1984; Michaloudi

and Papadopoulos, 1999). When activated (besides anaphy-

lactic reactions) mast cells are able to secrete with

compound exocytosis and piecemeal degranulation (Dvorak

et al., 1992). Moreover the activity of brain mast cells is

dependent on the quantity of sexual steroids (Wilhelm et al.,

2000) and in post partum female rats the number of mast

cells is dramatically increased (Silverman et al., 2000).

Their functioning is presumably involved in the develop-

ment of some conditions such as headaches or multiple

sclerosis (Rozniecki et al., 1997). Mast cells can migrate

quickly in and out of the brain tissue through the walls of

blood vessels and are able to release the above mentioned

various compounds. In migraines probably these cells

release vasoactive and proinflammatory products. In immo-

bilization stress most of the rat dura mast cells degranulated

(Theoharides et al., 1995) and mast cell protease I level was

found to be higher in the cerebrospinal fluid than in normal

condition. However there are no in vivo data available

concerning the possible physiological effects of these

secreted materials on neurons.

logy 171 (2006) 1 – 7

P. Kovacs et al. / Journal of Neuroimmunology 171 (2006) 1–72

Compound 48/80 (C48/80) is a well known mast cell

degranulator causing mass exocytosis similarly to the IgE

dependent mechanisms at the periphery and also in the brain

(Dimitriadou et al., 1990; Ibrahim, 1970). In doves intra-

muscular administration of C48/80 resulted in infiltration of

the blood–brain barrier (Zhuang et al., 1996), but only in

the medial habenula, where mast cells are localised. Only in

that area many degranulated mast cells were found. In

similarly vascularized structures of the brain where mast

cells were not found, signs of changes in blood–brain

barrier permeability were not seen.

By means of in vivo microiontophoretic application of

C48/80 and combined recording of neural activity we

investigated if (i) the stimulation of mast cells modifies

the unit activity of thalamic neurons and whether these

effects are stimulatory or inhibitory, (ii) there are any age- or

sex-dependent differences in these effects (iii) active,

degranulating mast cells are located in close approximity

of the recorded neurons.

Fig. 1. Scheme of the hypothetical working of the applied method.

Iontophoretically ejected C48/80 activates mast cells. Degranulating mast

cells affect surrounding thalamic neurons. Extracellular action potentials are

recorded by the central carbon fiber of the iontophoretic electrode. Control

drugs or dyes are ejected either to verify the right responsiveness of the

recorded neuron (GABA, KA), to point the electrode placement (PSB) or to

stain activated mast cells (neurobiotin).

2. Materials and methods

2.1. Animals and surgery

All experiments were approved by the Animal Care

Committee at our Institution (University of Pecs, Hungary)

and also matched international standards (NIH Guidelines).

Young, 6–8 weeks old (n =5 males and n =9 females), and

adult 16–20 weeks old (n =5 males and n =5 females)

CFY rats were used. Anaesthesia was induced with a

single injection of ketamine (100 mg/kg; Calypsol, RG,

Hungary). Stereotaxic brain targets were taken from the

coordinates of AP: �3.6 mm, ML: 2.6 mm from bregma

and V: 0.5–7.0 mm from dura according to Paxinos and

Watson (1997). In this brain section cortical, hippocampal

and thalamic neurons can be recorded from one vertical

track (Fig. 4).

2.2. Extracellular action potential recording and

iontophoresis

Seven-barrelled micropipettes were used for recording

neural activity and for microiontophoresis (Carbostar-7,

Kation-Scientific, MN, USA). The impedance of the

central recording channel was 0.4–0.8 MV (at 50 Hz),

and the impedance of the surrounding six drug-channels

were 10–70 MV. One of the drug-channels (filled with 0.5

M NaCl) was used for the application of a continuous

balancing current, while others were filled with the

bioactive substances or the applied dyes listed below. In

microiontophoretic experiments, the applied drugs were

dissolved in distilled water rather than in physiological

solution, to ensure that no other charged ions could be

ejected with the positive or negative direct current. After

registering extracellularly the spontaneous activity of the

neurons, we injected kainic acid (KA; Sigma, 50 mM

dissolved in distilled water) as excitatory and GABA

(Sigma, 50 mM, dissolved in distilled water) as inhibitory

controls. Right after administration of controls, C48/80

(Sigma, 100 mM dissolved in distilled water) was applied

for testing the possible effects of degranulating thalamic

mast cells on neurons (Fig. 1). GABA and C48/80 were

ejected as cations, while KA as anion, with 5–30 nA

balanced continuous currents. At the end of the electro-

physiological experiments the site of the electrode-tip was

marked iontophoretically with pontamine sky blue (PSB,

500 nA negative current for 30 min) to indicate the exact

place of the recorded neurons. Neurobiotin (n =3) was

used to fill neurons extracellularly in vivo (200–500 ms

pulses with 50–100 nA positive current for 30 min) as

described by Pinault (1996).

2.3. Data recording and statistical analysis

Extracellular action potentials (5–60 AV) were recorded

and passed through an analogue-digital converter (Power

1401, CED, Cambridge, UK) to an IBM-compatible micro-

computer. Spike sorting and data analysis were performed

by the Spike 2 software (CED, Cambridge, UK). Frequency

histograms were built and neuronal activity was displayed in

cycles per second (cps, equal with Hertz, Hz). Spike sorting

routines were run both on- and off-line and waveform

averages were displayed (TS.E.M.) to ensure that data were

always recorded from a single neuron. Before each session,

GABA or kainic acid was applied to verify the right

responsiveness of the recorded neuron. A neuron was

considered responsive to a drug ejection when its firing

rate changed T20% respective to its baseline frequency.

Statistics between pre- and post-treatment firing activity

were performed using one-way ANOVA and Student’s

paired and unpaired t-tests. The threshold for significance

Table 1

Effects of C48/80 on neuronal activity

Effect Thalamus Hippocampus Cortex

nneuron (%) Normalized effect

TSTDEV (n trials)

nneuron (%) Normalized effect

TSTDEV (ntrials)

nneuron (%) Normalised effect

TSTDEV (ntrials)

Young j 46 /68 (68) 6.18T4.55 (94) – – – –

9 < 16 /68 (23) 1.03T0.06 (29) 29 /30 (97) 1.01T0.10 (37) 4 /4 (100) 0.97T0.07 (4)

, 6 /68 (9) 0.32T0.13 (18) 1 /30 (3) 0.31T0.12 (3) – –

Adult j 11 /14 (79) 8.03T4.55 (19) – – – –

9 < 3 /14 (21) 0.96T0.10 (6) 3 /3 (100) 1.04T0.01 (4) 7 /7 (100) 1.02T0.14 (7)

Young j 2 /16 (13) 7.79T2.18 (6) – – – –

S < 9 /16 (56) 0.99T0.09 (21) 4 /4 (100) 1.01T0.03 (4) 5 /5 (100) 1.05T0.14 (10)

, 5 /16 (31) 0.28T0.13 (12) – – – –

Adult j 2 /20 (10) 4.98T3.15 (5) – – – –

S < 11 /20 (55) 1.02T0.08 (31) 9 /9 (100) 1.03T0.07 (10) 7 /7 (100) 1.04T0.09 (14)

, 7 /20 (35) 0.26T0.07 (7) – – – –

Aneuron=187 Atrials=341

Effects of C48/80 were significant in all mentioned cases ( p <0.01), j excitatory, , inhibitory, < no effect.

Fig. 2. Effects of iontophoretically applied mast cells degranulator C48/80

on neuronal activity, frequency histograms of three typical neurons. Control

drugs: KA as excitatory and GABA as inhibitory agents. (a) C48/80 causes

large excitations on thalamic neurons in female rats. (b) Effect of C48/80

leads to neuronal inhibition in male thalamus. (c) C48/80 does not alter the

baseline activity of hippocampal neurons. Abbreviations: Hz: Hertz, 1/s,

firing frequency of neurons; nA: nanoampere, ejection current intensity of

the applied drugs; sec: seconds.

P. Kovacs et al. / Journal of Neuroimmunology 171 (2006) 1–7 3

was set as p <0.01. Effects of applied compounds were also

expressed as ‘‘normalized effect’’ (Table 1, Fig. 3) showing

the discharge between the neuron’s baseline frequency and

the frequency changes under the drug treatments

(TSTDEV).

2.4. Histology

Rats were perfused with 4% paraformaldehyde, the brain

dissected and postfixed for 4 h at room temperature. Then

the fixed brain tissue was cut in a vibrotome at 25 Am,

sections were mounted on double subbed gelatinized slides

and mast cells stained with acidic toluidine blue (TB,

Sigma, pH 2) for 10 min. For total mast cell counts alternate

sections were mounted from the entire thalamus on double

subbed gelatinized slides and stained with TB. Cell counts

were done with the aid of an ocular grid and through a

camera lucida. Each cell either containing distinct granules

or a nucleus was marked in the outline of the thalamus. The

Abercrombie correction (Abercrombie, 1946) was per-

formed to assess total mast cell numbers. Calculation was

carried out with the following equation: N =2n(T /T +D),

where N is the corrected cell number, n is the uncorrected

cell number, T is section thickness, D is the mean cell

diameter. Although mast cells are mostly round, in the

young (6 weeks old) animals elongated cells were

frequently seen. Double staining experiments were also

carried out with anti-serotonin antibody (rabbit anti-5HT;

Sigma, 1 :5000; n =4 females) and TB to determine the

proportion of serotonin (5HT) —containing mast cells in the

investigated areas. Free floating sections were kept in the

primary antibody overnight at 4 -C, the secondary antibody

was goat anti-rabbit (1 : 100) followed by ExtrAvidin

complex (Sigma, 1 :200) for 4 h, finally stained with 3V3-Diaminobenzidine (DAB). Then sections were mounted on

gelatinized slides, stained with TB (15 min), dehydrated in

ascending ethanol series, cleared in xylene, and cover-

slipped with 1,3-Diethyl-8-phenylxanthine (DPX). The

iontophoretically applied neurobiotin was visualised with

DAB and these sections were immediately counterstained

with acidic TB.


3. Results

3.1. Iontophoresis

We recorded from 187 neurons and analysed 341

different drug ejection trials. In control situations, kainate

stimulated, and GABA inhibited the spontaneous neuronal

activity in every investigated brain regions. Administration

of C48/80 did not modify the activity of cortical (100%,

n =23 /23) or hippocampal neurons (98%, n =45 /46, Fig.

2c). However, ejection of C48/80 did have various effects

on single cell unit activity in the thalamus. These effects

were sex-dependent and did not show significant differences

between young and adult animals (Table 1, Fig. 3). In

females, C48/80 caused neuronal excitation in 70% (n =57 /

82, Fig. 2a) of the cases, or inhibited cells to a lesser extent

(7%; n =6 /82). In males, the same protocol caused hyper-

polarization more frequently (33%, n =12 /36, Fig. 2b)

while depolarization was rare (11%, n =4 /36). Fig. 3 shows

the percental distribution of the normalised effects between

the different groups in the thalamus. It can be seen that the

excitatory responses to C48/80 application were extremely

high in most cases (4.98x�8.03x of baseline). The sites of

the electrode-tips were finally marked with PSB and the

estimated placements of the differently responded neurons

were inserted in a blind stereotaxic slide of Paxinos and

Watson (1997). These responses were more frequent in the

upper thalamic regions –closer to the hippocampus– for

example in the lateral nuclear group of the anterior

subdivision (lateroposterior nucleus: LP; laterodorsal

nucleus: LD). In the deeper lateral subdivision (posterior

nucleus: Po; ventroposterior nucleus medial subnuclei:

VPM) the effects were less pronounced (Fig. 4).

Fig. 3. Effects of C48/80-activatedmast cells on thalamic neurons (-STDEV)

and their percental distribution depending on gender or age. The effects

are normalised to the averaged baseline activity (1) before the C48/80

treatment.

Fig. 4. The estimated placements of the differently responded neurons to

C48/80 ejection. Red circles: mast cells depolarize neurons, blue squares:

mast cells hyperpolarize neurons, green squares: C48/80 does not alter

neuronal firing rate. The blind outline of the brain section comes from

Paxinos and Watson (1997). Abbreviations: hip: hippocampus; thalamic

nuclei: CM, Central medial nucleus; LD: laterodorsal nucleus; LP:

lateroposterior nucleus; MD: mediodorsal nucleus; Po: posterior nucleus;

PV: paraventricular nuclei; VPM: ventroposterior nucleus medial subnuclei.

3.2. Histology

We have found many partially or fully degranulated mast

cells around the recorded thalamic neurons (Fig. 5) but not

around neurons in cortical or hippocampal areas nearby the

electrode track. Neurobiotin is widely used to stain neurons

but in our experiments we were able to stain only activated

mast cells with this technique. In and around degranulating

Fig. 5. (a and b) Three active, degranulating mast cells (black arrows) in

different focal plains in the recorded area. (a) Released mast cells products

do not bind neurobiotin and are stained blue (black arrowheads) with acidic

TB. (b) The iontophoretically injected neurobiotin binds to the proteogly-

cans of mast cells granules. Labelled brown proteoglycans can be seen in

and around the activated mast cells (white arrows). (c) The position of the

electrodes is visualised with PSB (asterisk). In the close proximity two mast

cells can be seen, from which one picked up PSB (black arrowhead). The

second one is labelled with only in vitro applied TB (black arrow). Scale

bars: 10 Am.

Fig. 6. Mast cells in and around a capillary after immunostaining with

serotonin and counter staining with TB. Some of the cells are double

stained, but mostly only TB positive cells were visible (asterisk). In most of

the cells only some granules were immunopositive but strong 5HT-

positivity was also seen in few cells (arrows). Mast cells occur in clusters

and in many sections 5HT-positive and negative cells were lying parallel to

each other (arrowhead). Scale bar: 50 Am.

Fig. 7. 5HT-positive mast cell in the rat thalamus. The cell lies at the edge of

a capillary, while extending a huge filopodium (arrow) into the brain, filled

with 5HT-positive granules. Several immunopositive granules (arrowheads)

are also visible far from the cell body. Scale bar: 10 Am.


mast cells, probably proteoglycan products bound to in vivo

iontophoretically applied neurobiotin were seen, while other

released products were only stained with acidic TB in

histological sections (Fig. 5a,b). Around the PSB-labelled

areas C48/80 activated mast cells accumulated PSB, while

the more distant, probably unaffected mast cells were

stained only with TB (Fig. 5c). Total mast cells numbers

ranged from 3550 to 6900 in the female rat thalamus (n =5).

Mean mast cell diameter was 14.25T2.89 Am. The size of

cells depended on their degranulation state. With double

staining experiments we have found that anti-5HT antibody

labeled only 8.29% to 10.06% (Fig. 6), but in one animal

40% was found to be 5HT-positive of the TB positive mast

cells in females (Fig. 7). Most of the stained cells were in

clusters, where in one cluster only few 5HT-positive cells

were visible (Fig. 6). Immunoreactivity was seen mostly in

some of the granules of the cells, in cells which were located

in the lumen of thalamic capillaries all the granules seemed

to have strong serotonin positivity.

4. Discussion

Injection of C48/80 modified the activity of thalamic

neurons, whereas it had no effect on hippocampal or cortical

neurons in either of the genders, possibly because there are

no histologically detectable mast cells in these brain areas in


the rat (Bugajski et al., 1995). Modification of firing activity

of thalamic neurons could be either excitatory (more typical

of females), or inhibitory (more typical of males). Depola-

rizations were extremely strong in most cases, maybe

because mast cells secreting compounds depolarized several

surrounding neurons which had been ‘‘silent’’ until the

activation. In these cases, non-specific, background, multi-

unit-like excitations also appeared in the frequency histo-

grams. Gender specific reactions may be related to the higher

number, and the differently stored and ejected bioactive

compounds of mast cells in the female thalamus, especially

to those of serotonin and histamine (Asarian et al., 2002;

Atkins et al., 1993; Bradesi et al., 2001; Crivellato et al.,

1997; Csaba et al., 2003; Goldschmidt et al., 1984). There

were no significant age-dependent differences in the effects

suggesting that the stored compounds of mast cells are

almost the same in different ages. The reason why mast cell

numbers are greater in females than in males is unclear. In

human subjects, in the first hour after cutaneous allergen

injection, the amount of histamine released into the

cutaneous tissue was higher in males than in females (Atkins

et al., 1993), while in the intestine of rats histamine level

was found to be higher in the mast cells of females than of

the males (Bradesi et al., 2001). Also in adult rat peritoneal

mast cells serotonin content was significantly higher in

females than in males (Csaba et al., 2003). Peritoneal mast

cells are very similar to brain mast cells morphologically,

and are able to enter the brain (Silverman et al., 2000).

Degranulating mast cells were detected in close proximity of

the electrode-tip showing that C48/80 affected mast cells

were close to the studied thalamic neurons. Degranulation

and mast cell activation by C48/80 was also demonstrated

by either in situ PSB- or neurobiotin staining. To much of

our surprise extracellularly applied neurobiotin could stain

activated mast cells after C48/80 application. Labelled nerve

cells could not be detected around the recorded area. Under

these conditions mast cells seem to have much more

intensive vesicular recycling then neurons and exocytosing

mast cell granules become swollen while stored products

leave the granules. The average halftime of the ampero-

metric spikes measured in granule exocytosis was found to

be approximately 150 ms (Marszalek et al., 1997).

Crivellato et al. (1997) demonstrating that upon granule

exocytosis positively charged molecules compete to bind to

the negatively charged matrix of proteglycans. The mole-

cules bound to granule matrix are quickly endocytosed and

can be visualised with microscopy. In this way, mast cells

may pick up neurobiotin faster than neurons, so this unusual

staining can be due to the engulfment of neurobiotin during

the recovery of granule matrix.

Further investigations should answer the question what

kind of secreted neuroactive substances are responsible for

these effects. Serotonin is known for its inhibitory effects on

brain neurons and it is clear from our findings, that the ratio

of inhibitory effects measured on thalamic neurons and the

number of 5HT-positive mast cells is quite parallel,

especially in young females. In rat thalamic–hypothalamic

slices C48/80 caused 5HT release from mast cells (Mar-

athias et al., 1991). Neuronal depolarization in these

experiments resulted in somatostatin release. Somatostatin

reduced subsequent C48/80 stimulation. Other studies

suggest that C48/80 could activate only histamine release

from mast cells (Bugajski et al., 1995; Ikarashi and

Yuzurihara, 2002), so maybe histamine is responsible for

the excitatory effects through activation of postsynaptic H1

and H2 receptors which finally depolarize neurons (Brown

et al., 2001). In other studies the biochemical effect of C48/

80 on mast cells was also moderately diminished by

intracerebro-ventricularly applied H1 and H2 receptor

antagonists (Gadek-Michalska et al., 1991), and intracere-

bro-ventricularly applied C48/80 causes the same behav-

ioural changes that histamine does in chickens (Kawakami

et al., 2000). Furthermore in vitro studies of the guinea-pig

heart demonstrated already that histamine release from mast

cells increased the excitability of intracardiac neurons

(Powers et al., 2001). However iontophoretically adminis-

tered histamine reduced the firing rate of anterior and

intralaminar thalamic neurons (Sittig and Davidowa, 2001).

To summarise our findings, this study presents an in situ

functional observation that mast cells may modify neuronal

activity under normal physiological conditions in the rat

thalamus. This modification is sex-influenced and restricted

to specific thalamic subregions. The effect is mostly

excitatory and causes a large frequency increase of neuronal

firing rate in females, but it tends to be inhibitory in males.

Further analysis of this cross-talk of mast cells and neurons

is required to discover more about the possible transmitters

and modulators and the physiological background modify-

ing connection between the elements of the immune system

and the neurons of the brain.

Acknowledgements

The authors thank Dora Molnar for technical assistance

and Dr. Robert Gabriel for critically reviewing the manu-

script. Marta Wilhelm is in receipt of a Janos Bolyai

Scholarship. Financial support was given by the MTA-PTE

Adaptational Biology Research Group.

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Mast cells modulate maintained neuronal activity in the thalamus in vivo

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