Chronic dietary lithium inhibits basal C-fos mRNA expression in rat brain

PTOLJNeuro~Psychopharmncol.

Pergamoa

& Biol. Psychiat. Copyright Printed

0278-5846(95)00235-Q

1995. Vol. 19. pp. 1177-I 0 1995 Elsevler

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CHRONIC DIETARY LITHIUM INHIBITS BASAL C-Jos mFtNA EXPRESSION IN BAT BRAIN ALEKSANDER

A. MATHE’,

JEANNETTE

C. MILLER* and CARINA STENFORS’

’ Karolinska Institute, Institution of Clinical Neuroscience, Department of Psychiatry, St. Gorans Hospital, Stockholm, Sweden and ‘Millhauser Laboratories of the Department of Psychiatry, New York University Medical Center, New York, NY, USA and 3Karolinska Institute, Institution of Laboratory Medicine, Department of Ciinicai Chemistry, Karolinska Hospital, Stockholm, Sweden

(Final form, June 1995)

Abstract Math& Aleksander A., Jeannette C. Miller and Carina Stenfors: Chronic Dietary Lithium Inhibits Basal c-fos mRNA Expression in Rat Brain. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1995,19(7): 1177-1187. 1. Lithium is the most effective prophylactic agent used in the treatment of bipolar disorder. Although the acute effects of lithium include an inhibitory action on the phosphatidylinositol (PI) system, the longer term effects on signal transduction processes linked to this system are poorly understood. 2. An important consequence of activation of receptors linked to the PI pathway is activation of protein kinase C (PKC), which is involved in the induction of the proto-oncogene, C-$X. 3. The authors hypothesized that chronic lithium treatment, by inhibiting signaling through the PYPKC pathway, might alter the expression of fos. 4. It was found that basal expression of c-fos was significantly reduced in cortical, hippocampal and hypothalamic brain areas of rats fed dietary lithium for 4 weeks. 5. The present results suggest that some of the effects of chronic lithium treatment may be mediated by alterations in signal transduction mechanisms linked tofos expression. Keywords: c-fix, depression,

lithium, mania, signal transduction.

Abbreviations: CAMP responsive element (CRE); CAMP responsive element binding protein (CREB); diacylglycerol (DAG); guanosine triphosphate (GTP); immediate early gene (IEG); inositol 1,4,5triphosphate (lP3); phosphatidyl inositol (PI); protein kinase A (PKA); protein kinase C (PKC); phospholipase C (PLC); serum response element (SRE); serum response factor (SRP)

1177

1178

A.A. MathP et al Introduction

The most conspicuous

clinical property

preventing both up and downward lithium produces

its anti-manic

of lithium is its “stabilizing” effect in major affective disorders,

mood oscillations in bipolar disorder. and anti-depressive

effects are not entirely understood,

ample literature on lithium’s effects on the phosphoinositol The PI cycle represents

an important

GTP dependent

hydrolysis

producing the second messengers, calcium, and diacylglycerol Berridge and Irvine, 1984).

4,5-biphosphate

inositol 1,4,5triphosphate

(DAG), which activates

although there is

that serve to modulate intracellular

1984). Neurotransmitters

of phosphatidylinositol

by which

(PI) system (Post and Chuang, 1991 review).

source of second messengers

calcium and protein kinase activity (Berridge,

The precise mechanisms

that activate the PI cycle induce

and activate phospholipase

C (PLC),

(IP3), an important mobilizer of intracellular

protein kinase C (PKC)

(Sherman,

1991 review and

There is evidence that lithium may produce its actions by reducing signaling

through these second messengers

(Lenox et al., 1992; Manji et al., 1991,1993) and by attenuating

G-

protein mediated function (Ebstein et al., 1980; Avissar et al., 1988; Belmaker et al., 1991; Li et al., 1991, 1993).

Recently,

attention

has been given to a possible

influence

of lithium on the proto-oncogene,

c-fos

because this gene is known to be rapidly activated by agonist signaling through the PLC/DAG/PKC adenylate cyclase/cAMP/cAMP-dependent other

protein kinase (PKA) second messenger

systems.

C-fos and

immediate early genes (IEGs) have been shown to play a role in neuronal cell function and are

induced in rat brain by a variety of neurotransmitters review). The fos and &n

protooncogenes

complex which binds cooperatively et al., 1988; Sassone-Corsi

encode

and extracellular stimuli (Morgan and Curran, 1991 nuclear phospho-proteins

that form a heterodimeric

to a DNA regulatory element known as the AP-1 binding site (Franza

et al., 1988a). This sequence has many variations and is present in both positive

and negative regulatory elements of a number of target genes (Rauscher et al., 1988; Gizang-Ginsberg Ziff, 1990) and thefos gene transcription

promoter

(Sassone-Corsi

signal transduction

et al., 1988b). thereby the potential to activate or repress

effects of the longer term consequences processes.

of chronic lithium treatment

Weiner et al., (1991) have previously

lithium treatment enhanced a muscarinic agonist induced c-fos response potential role for the IEGs in longer term adaptation expression,

particularly neuropeptides,

Because of the

of neuronal function and regulation of target gene

et al., 1994; Stenfors

the effect of chronic dietary lithium treatment

brain regions of the rat. Considering

on post

shown that subchronic

in the rat brain.

and the role that some neuropeptides

(Math6 et al., 1991, 1994; Jousisto-Hanson investigated

and

exists.

There are few established receptor

and

may play in mood disorders

et al., 1992,1994),

on the basal expression

of

the authors

c-fos in various

the apparent dampening effects of lithium on the PI pathway and on

G protein coupled function, the authors hypothesized

that lithium might reduce c-fos expression.

Clfos expression

1179

inhibited by lithium

Methods Animal Treatment Male Sprague-Dawley

rats (ALAB, Solna), initially weighing 120- 130 g, were used in all investigations.

The rats were housed at constant

room temperature

(21 f l”C), with a 12:12 hour light-dark cycle.

had free access to water, standard rat food or dietary lithium. weeks of dietary lithium) were examined in three experiments

The effects of (I, II and III).

chronic treatment

Rats (four

In the pilot experiment,

I.

three groups of animals (n=3 each) were fed identical amounts of standard rat chow, or chow to which lithium sulfate (Astra AB, Sodertalje)

in doses of 1.29 g/kg or 2.lY g/kg was admixed.

treatments were repeated in experiment

II (n=8,8,8) and in experiment

These lithium

III (n=S,5) in which only one dose

12.1Y g/kg) of lithium was given. In a separate mvestigation

using identical procedures

the mean serum lithium concentrations high lithium concentrations,

(Mathe et al., unpublished data) we showed that

were approximately

respectively.

0.4 and 0.6 mEq/L for the rats fed the low and

Along with regular tap water, all animals had free access to a

bottle containing 0.9% NaCl to prevent lithium toxicity (Ellis and Lenox, 1990). After the four week lithium regimen,

the animals were sacrificed

by decapitation,

the brains quickly

removed, and regions dissected according to Glowinsky and Iversen (1966). The tissues were immediately frozen in powdered dry ice and stored at -80°C until shipment for analysis of cTfos mRNA expression,

These studies were approved by the Ethical Committee all experiments,

the rats groomed

were observed.

No weight differences

for Animal Experiments,

Karolinska Institute.

In

normally and no gross behavioral changes or signs of lithium toxicity were observed in peripheral organs or in the brain regions between

the treatment groups (Mathk et al., 1994). Northern AnaIysis of c-fos mRNA Exoression Total RNA was prepared as previously described isothiocyanateCsC1 MOPS/formaldehyde (Stratalinker,

procedure

of Chirgwin

gels, and blotting

Stratagene,

La Jolla, CA).

(Miller, 1990) using a modification

et al. (1979).

onto nitrocelluose

After

of the guanidinium

electrophoresis

on 1% agarose

filters, the RNA was UV auto-cross-linked

The RNA blots were prehybridized

and hybridized

at 42°C as

previously described (Miller, 1990) with a 1.0 kb Pst I fragment of clfos cDNA (mouse) radiolabeled with ‘*P-dCTP (Random Primer Extension

System, DuPont, Boston, MA).

probe ranged from 1.3-2 x 10’ dpn+tg. simultaneously

The specific activity of the c-fos

RNA recovery for each sample was assessed

by reprobing

or

probing samples with a random primed 32P-dCTP labeled 564 bp fragment of rat cyclophilin

cDNA as a control “unregulated”

gene. Filters were washed to a stringency of 0.2 x standard saline citrate

buffer (1 X SSC = [0.15 M NaCl, 15 mM Na3Citrate-ZH?O])

in 0.1%

SDS for 1 hr at WC,

sealed in

1180

A.A. Math6 et al.

plastic bags and exposed to Kodak XAR-5 film for 18-36 hr. Data Analysis The intensity of hybridization the autoradiograms

using an Image Analysis Video Densitometric

c-fos were corrected sample.

for the mRNA species was quantitated

for recovery

The meanfislcyclophilin

data from the three experiments,

ANOVA

a fislcyclophilin

f sd. for each treatment group was calculated. thef’slcyclophilin

analysis of

The density units for

System (MCID).

and quantity of RNA by calculating

vehicle values (defined as 100% k s.d.) using either one-way

by video densitometric

ratio for each

In order to combine the

ratios of the lithium treated samples were compared to

to calculate percent of control.

and post hoc comparisons

Statistical analyses were made

by the Student-Newman-Keuls

procedure

(Sigmastat) or the Student’s t-test (Sigmastat).

The results of chronic lithium exposure

on c-fos expression

are shown in Table 1. In experiment I, no

significant effect of chronic lithium was found in the frontal cortex, striatum or hypothalamus,

Significant reductions in c-

there was an overall tendency of lithium to reduce c-fos mRNA in these areas. fos mRNA were found, however,

in the occipital cortex and hippocampus.

although

In experiment

II, both doses

of dietary lithium significantly reduced c-fos in frontal cortex, occipital cortex, striatum and hippocampus, but no significant effect was seen in the hypothalamus. higher dose of lithium in the pituitary. experiment

III,

hippocampus;

A dose-related

A significant reduction

no significant

effect was seen in occipital cortex,

in the frontal cortex and striatum

or pituitary.

Northern blots from experiment

III are shown in Fig. 1. When all the data were combined,

found to significantly

c-fos expression

hypothalamus

decrease

(Fig. 2). A dose-related

In

effect was only observed in the hippocampus.

lithium was again found to reduce c-fos mRNA expression however

was only seen with the

in frontal cortex,

occipital

cortex,

The

lithium was

hippocampus

and

effect was only evident in the hippocampus.

Discussion Short and Long-term Effects of Lithium on c-fos The major finding from this study is that chronic lithium treatment reduces the &@ expression in cortical, hippocampal perturbation.

and hypothalamic

of c-fos

brain areas of rats in the absence of any pharmacological

To date only a few papers on the effects of lithium on c-fos have been published.

Weiner et

al. (1991) reported that acute and subchronic lithium treatment of rats enhances cortical c-fos expression elicited by muscarinic, Ml, receptor response

is attenuated

activation; however this lithium augmenting of an agonist mediated

with repeated lithium treatment,

a result consistent with the refractoriness

of fos

C-fos expression

inhibited

by lithium

1181

Table 1 Effect of Chronic Dietary Lithium on c-fos Expression

Frontal Cortex Expt. I (n=3,3,3) Expt. II (n=8,8,8) Expt. III (n=5,5) occipital cortex Expt. I (n=3,3,3) Expt. II (n=8,8,8) Expt. III (n=5,5) Striatum Expt. I (n=3,3,3) Expt. II (n=7,7,7) Expt. III (n=5,5) Hippocampus Expt. I (n=3,3,3) Expt. II (n=8,8,8) Expt. III (n=5,5) Hypothalamus Expt. I (n=3,3,3) Expt. II (n=4,3,3) Expt. III (n=5,5) Pituitary Expt. II (n=3,4,4) Expt. III (n=4,4)

0.768 k 0.034 0.606 + 0.128 0.212 f 0.040

0.722kO.100 0.507 f 0.052* ND

0.758 + 0.072 0.498 f 0.02 1* 0.117 f 0.078*

0.880 k 0.117 0.540 * 0.045 0.539 + 0.102

0.614 f 0.062* 0.460 f 0.053* ND

0.725 f 0.040 0.467 f 0.039* 0.413+0.110

1.161 f0.235 0.626 + 0.030 0.264 f 0.039

1.138 f0.099 0.525 f 0.055* ND

1.293 f 0.256 0.505 f 0.049* 0.274 + 0.037

0.7 12 + 0.060 0.918 + 0.044 0.25 1 + 0.040

0.599 f 0.018* 0.861 + 0.055* ND

0.6 15 + 0.050* 0.804 + 0.042*# 0.191 f 0.025*

0.733 k 0.042 0.576 k 0.104 0.498 rt 0.072

0.692 + 0.068 0.504 + 0.030 ND

0.633 + 0.054 0.526 + 0.094 0.377 f 0.038*

0.582 f 0.049 0.495 f 0.107

0.544 + 0.017 ND

0.508 zk0.029* 0.434 I!z0.134

Data reported as relative mEWA levels (c-fos/cyclopbilin). Experiments I and II, One-way ANOVA, posthoc comparison Student-Newman-Keuls method, *significantly different from vehicle treated, Pc.05; #significant lithium dose effect, P<.O5). Experiment III, Student’s t-test, *significantly different from vehicle treated, Pc.05.

induction

to repeated

treatment

may decrease

stimuli

in the CNS (Morgan and Curran, 1991). Thus, more prolonged

the fos response

lithium, per se, on c-fos expression

to agonists.

On the other hand, the longer term effects of

have apparently not been previously reported.

Lone Term Lithium Action on Signal Transduction

The molecular and/or genetic components

Pathways Linked to c-_os

contributing

to the expression

of manic depressive

not well understood

although a number of hypotheses

actions of lithium.

The most studied mechanism by which lithium is believed

effect in mood disorders

involves its effects

suggested that bipolar disorder

lithium

illness are

have been presented based on preclinical and clinical

on the PI/PKC

may be a result of overactivity

to exert

signal transduction of neurotransmitter

its therapeutic

pathway. signaling

It has been pathways

1182

A.A. Math6 et al.

Fig. 1. Northern Blots of c-fos mRNA Expression in Various Brain Regions After Chronic Dietary Lithium (f’rom Experiment III): 10 ttg of total RNA was analyzed from indicated brain regions [see Figure 2 for abbreviations] from rats after 4 weeks of standard rat chow (Vehicle treatment on the left) or 2.2 g/kg/day of lithium in the chow (Chronic lithium treatment on the right) as described in the text. The positions of 28s and 18s ribosomd RNAs, c-fos and cyclophilin are indicated. Each lane represents RNA analyzed from a single rat.

linked to the PYPKC second messenger

system (Lachman and Papalos, 1989; Hudson et al., 1993).

inhibition by lithium of the PI/PKC pathway and mobilization

of calcium might be expected to result in a

reduction or attenuation of PI linked neuronal activity, and in this way produce its therapeutic C-fos transcription

is highly regulated

and is subject to induction

systems and specific protein kinases which phosphorylate located in the promoter element

region of

(CRE), and serum response

(CAMP responsive 1991 review).

the fos gene. element

by activation

action..

of second messenger

proteins that converge on DNA regulatory sites,

Two important

sites are the Ca”-CAMP

(SRE) which recognize

element binding protein) and SRF (serum response

the transcription factor) respectively

responsive

factors CREB (Herschman,

There is substantial evidence from studies in cultured cells that signal transduction

in response to a number of different ligands (growth factors, serum, depolarization) the SRE or CRE elements of the fos promoter Activation of PKC-dependent

to induce its transcription

pathways results in fos induction mediates

cAMP/PKA

and Greenberg,

speculate

that decreased

pathways

appear to converge on

(Herschman,

199 1 for review).

mediated by transcriptional

bind to the SRE, while the CRE element 1990). Thus, the authors

Thus,

factors that

and calcium induction of c-fos (Sheng PKC activity by lithium might serve

C-,fos expression

2oo 2

/-

a

175-

m

E 5 0 ?J o\o v7 1=

150

-

125

-

100

-

inhibited

hy lithium

I183

___

CONTROL CHRONIC

Li (1 .3

CHRONIC

l.i (2 2 gm/kg)

FC

HT

gm/kq)

PIT

Fig. 2. Effect of Chronic Dietary Lithium on c-fos mRNA Expression in Various Brain Regions )41, = 5.628, Pc.007; Newman-Keuls, [Combined Data]. ANOVA revealed, FC = frontal cortex (F_, *P<.OS vs. control); OC = occipital cortex (F ~.4~)=I 1.738, Pc.001; NewmanKeuls, *P<.O5 vs. control); ST= striatum (FZ.XT= 2.455, P=O.lO); HC = hippocampus (F2,40=14.686, P<.OOl: Newman-Keuls, *P<.OS vs. control and “Pc.05 between doses); HT == hypothalamus (F?x,= 6.108, P=.OO7: Newman-Keuls, *P<.O5 vs. control); PIT = pituitary (F2.r6= 1.307, P=.298).

There

is support

for

this

hypothetical

to inhibit basal transcription

of C-$X.

lithium could affect c-f&.

Lenox et al. (1992) found a major reduction

products

in rat hippocampus

htppocampus

after chronic

although other mechanisms

such as regulation

by which

in two PKC phosphorylation

PKC activity has been observed

lithium and decreased

after lithium (Manji et al., 1993).

mechanism

in

Such actions of lithium may partly explain our tindings, of c-fos mRNA stability and the role of other factors,

including Fos and Fos related proteins, in repressing c-fos transcription

(Sassone-Corsi

et al., 1988b; Shaw

et al., 1989) cannot be ruled out.

There is also evidence suggesting

the potential for cross talk bctwcen the SRE and CRE elements of the

c-fos promoter which may be affected by lithium. Li et al. (1991) found a significant reduction in cortical Cc&l,

Gee-2 and Gs mRNAs from rats fed dietary lithium for 21 days.

decreased

levels of mRNA and protein for Gai- l,-2, but observed

How lithium affects the transcriptional known,

although

Cohn et al. (1991) also found

an upregulation

regulation of c-fos linked to the cAMPiPKA

Divish et al. (1991) reported

receptor activators of CAMP in PC12 cells.

no effect of

of adenylate cyclase. path in rat brain is not

lithium on c-fos expression

It is apparent from the data on G-protein

induced by

function, PKC and

cAMP activity, and the results of the present study that a clearer ptcturc of the mechanisms involved in the action of lithium, vis a vis c&s, contributions

requires

of both the cAMP/PKA

Functional Significance

further

and PJ/DAG/PKC

and a better- understandmg

signal-transduction

pathways.

Fos protein in specific neurons.

mouse have shown that Fos-1acZ fusion protein

neurons of the cortex and hippocampus

(Smeyne et al., 1992).

mechanisms.

expressed

in discretc

It would be of considerable

interest to

in these areas, particularly,

that are also altered by chronic lithium (Math6 et al., 1991, 1994;

et al., 1994; Zachrisson et al., 1995) and which may be targets for regulation by Fos/Jun

Although the specific neuronal sites at which the therapeutic

yet unknown, important

neuropeptides

Recent studies in thefos-

is continuously

determine whether chronic lithium affects Fos protein in neuronal populations

Jousisto-Hanson

the

in the present study, after chronic lithium, are relatively small and it is not

yet known whether such treatment also reduces

neurons expressing

of

of C-&X Reduction bv Chronic Lithium

The reductions seen in cfos,

/acZ transgene

investigation

the hippocampus,

subcortical

loci (Post et al., 1992 review).

actions of lithium occur are as

and cortical areas of the limbic system are almost certainly These areas are believed to be central to the expression

ot

emotion, mood and associative thinking, and may be disturbed in mania and depression,

Conclusion Chronic lithium treatment manner.

appears to reduce the basal expression

A reduction in c-fos expression

is compatible with previously observed attenuations

mediated function and in PKC mediated activity of the PI pathway. basal expression

of

clfos are biologically

mood remains to be determined. properties

in G-protein

Whether these modest reductions

significant or relevant to the stabilizing action of

Clinical effects

of lithium have a distinct

time course.

are apparent within one to two weeks following initiation of treatment,

effects in both mania and depression

require considerably

molecular events underlie these clinical phenomena. adaptations

of c-fos in brain in a region-specific

longer periods.

lithium on Anti-manic

while the prophylactic

It is conceivable

Further molecular characterizations

to chronic lithium could be helpful in the development

in

that different

of post receptor

of novel anti-manic and anti-depressant

drugs.

Acknowledemenis This study was supported

by the Swedish Medical Research Council 10414, the Theodore

Stanley Foundation, and the Karolinska Institute Research Fund.

and Vada

C-./bs rxpression

inhibitrd

by lithium

1185

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of a ,fos-1ac.Z

STENFORS. C., SRINIVASAN, G.R., THEODORSSON, E. and MATH& A.A. (1992) Elcctroconvulsivc stimuli and brain peptides: effect of modification of seizure duration on neuropeptidc Brain Res. 5’)6:241-258. Y, ncurokinin A, substance P and neurotensin. STENFORS, C., MATHJ$ A.A. and THEODORSSON, E. (1994) Repeated changes in neuropeptide Y, neurotensin and tachykinin concentrations Psychopharmacol. & Biol. Psychiatry. u:201-209.

electroconvulstve in time. Prog.

WEINER, E.D., KALASAPUDI, V.D., PAPOLOS, D.F.. and LACHMAN, H.M. augments pilocarpine-induced fos expression in rat brain. Brain Res. 553: I 17-122.

(1991)

stimuli: Neuro-

Lithium

ZACHRISSON, O., MATH& A.A., STENFORS, C. and LINDEFORS, N. (1995) Region-specific effects of chronic lithium administration on neuropeptide Y and somatostatin mRNA expression in the rat brain. Neurosci. Lett., in press.

Inquiries and reprint requests should be addressed to:

Alcksander A. Math& M.D., Ph.D. Karolinska Institute Institution of Clinical Neuroscience Department of Psychiatry, St. Gorans Hospital, S - I 12 81 Stockholm, Sweden