Mutant Taiep rats exhibit an increase in D

ELSEVIER
Brain Research 956 (2002) 24-29
www.elsevier.com/locate/brainres
Researchreport
Mutant Taiep rats exhibit an increasein D
Gonzalo Floresa,*, Julia Floresa,Raul Menac,Jaime Valenciab
'Lob. de Neuropsiquiatría, Instituto de Fisiología, Universidad Autónoma de Puebla, 14 Sur 6301, San Manuel, CP 72570, Puebla, Mexico
bLab. de Fisiología de la Conducta. Instituto de Fisiología, Universidad Autónoma de Puebla, Puebla, Mexico
'Departamento de Fisiología, Biofísica y Neurociencias. Centro de Investigaciones y Estudios Avanzados del IPN. Mexico D.F.
Accepted 25 June 2002
Abstract
Previousreportshave shownthat fue Taiep rat developa progressiveneurologicalsyndromecharacterizedby tremor, ataxia,irnmobility
episodes,audiogenicseizuresand hind limb paralysis.Here we have investigatedwhetherdifferencesin levels of doparnineDI-like and
D2-like receptorscould be correlatedwith fue progressionof this neurologicalsyndrome.Comparativeautoradiographicstudy of Taiep
and Sprague-Dawley(SD) rats at level of basalganglia and limbic subregionwere undertakenin 3- and 9-month-oldrats. The Taiep rats
exhibited a higher level of DI receptorsin the basalganglia subregionscomparedto SD. However,there were no differencesin the level
of DI receptorsin fue limbic subregionsbetweenfuesetwo strains.As comparedto fue SD rats, fue Taiep rats did not appearto change
levels of D2-like receptors.Thesedata suggestthat the differencesin DI receptorsin fuesetwo strains rats may in part contribute to
developfue doparninerelated symptomsseenin fue mutant rat, such as tremor, which is the earliest sign of fue Taiep rat syndrome.
@ 2002EIsevierScienceB.V. AII rights reserved.
Theme: Oisorders of !he nervous system
Topic: Neurodegenerative disease: rnyelin defects and neurotransmitters
Keywords: Taiep rat; Caudate-putarnen; External segment of fue globus pallidus; Substantia nigra pars compacta; Doparnine receptor; Myelin defect
1. Introduction
The Taiep rat (acronymfor trembling, ataxia,immobility
episodes,epilepsy and paralysis) [19] is a myelin mutant
Sprague-Dawleyrat, in which an early defect in development of the intracellulartransportof myelin componentsis
presentresulting in an abnormal myelin formation and a
subsequentprogressivedysmyelinationof fue centralnerve
system(CNS) axons [5,21].
Tremor is fue first neurologicalclinical sign in fue Taiep
rat and characteristicallyappearsat fue ageof 1 month. By
fue 4th month of age, locomotor ataxia becomesevident.
Immobility episodesappear at the age of 5-6 months.
Audiogenicseizuresand hind limb paralysisusually appear
after fue age of 10 months old [19]. All these motor
*Corresponding author. Tel.: +522-244-1657; fax:
E-mail address: gflores@siu.buap.mx (G. Flores).
0006-8993/02/$
- see front matter
PTT: SOOO6-R991(O2)O1414-0
-522-233-4511
alterationsin the mutant rat mar be related with dysfunctions of basal ganglia [6].
In general, DA receptors are classified in two broad
farnilies, namely fue D1-like (DI and D5) and D2-like
(D2, D3 and D4) receptors[16,25,33].Both fue DI andthe
D2 receptorsare abundantlyexpressedand widely distributed throughoutstriatal and limbic doparninefields including fue nucleus accumbensand the olfactory tubercle
[12-14]. Stimulationof fue D1-like receptorsincreasesfue
oral stereotypic behaviors in the animals but has poor
direct influenceon fue locomotor activity [23]. Conversely,
activation of the D2-like receptorswith fue agonist quinpirole results in a marked increasein locomotion [10].
Recent behavioral reports suggestthat Taiep rats have
altered DA function in fue nigrostriatal DA systemcompared with SD rat [35,36]. In the present study, we
investigated,by autoradiography,fue regional distribution
of DA D1-like receptor and DA D2-like receptorsin fue
basalganglia and limbic systemof Taiep rat and compared
with wild Sprague-Dawley(SD) rat at 3 and 9 monthsof
age.
@ 2002 EIsevier Science B.V. AII rights reserved.
G. Flores et al. I Brain Research956 (2002)24-29
2. Material and methods
Male Taiep and Sprague-Dawleyrats of 3 and 9 months
old used in this study were obtained and bred in OUT
facilities. Animals were group-housed(threeper cage)in a
temperatureand humidity controlled environment, on a
12-12 h light-dark cycle with free accessto food and
water. All experimentalproceduresdescribedin this study
are in accordancewith the guidelines of fue Laws and
Codesof Mexico in The SeventhTitle of fue Regulations
of fue GeneralLaw of Health RegardingHealth Research.
Animals were sacrificed by decapitation and brains
rapidly removed, frozen in isopentane maintained at
-40 °C and storedat - 80 °C until use.Frozenbrillos were
sectionedat 15 ¡Lm thicknesson fue sagittal plan using a
Leitz cryostat.Sectionswere collectedon cleaned,gelatincoated glass slides (four sectionsI slides), thaw-mounted,
desiccatedunder vacuum at 4 °C, overnight, and then
storedat -80 °C until fue day of the experimento
Sagittal brillo sectionstaken at fue level of fue nucleus
accumbens,caudate-putamen,entopeduncularnuclei and
substantianigra (plate 81-82 ofPaxinos and WatsonAtlas,
[26]) were used in fue following protocols. For Dl-like
receptorsbinding, sectionswere first preincubatedfor 10
min at room temperaturein buffer containing 50 mM
Tris-HCl pH 7.4,154 mM NaCl, 1 mM EDTA and 0.1%
bovine serum albumin. Sections were then incubated for
90 min at room temperature in same buffer with the
addition of 1 nM [3H]-SCH-23390(74 Ci/rnmol) and 30
nM ketanserin (to block possible binding of ligand to
serotonergic5-HT2 sites). Non-specific binding was determined on adjacent brain sections by adding 1 ¡LM
(+ )-butaclamolto fue buffer. Incubationswere terminated
by dipping the slides in ice-cold buffer followed by two
consecutive10 min washesin buffer. After a final dipping
in ice-cold distilled water, slides were dried at room
temperatureand apposedto [3H]-Hyperfilm for 7 days,
along side microscalescalibrated tritium standards.
For D2-like binding, fue slides were first preincubated
for 10 min at room temperaturein buffer containing 50
mM Tris-HCl pH 7.4, 120 mM NaCl, 1 mM EDTA, 5
mM KC1, 1.5 mM CaClz and 4 mM MgClz. Sectionswere
then incubatedfor 2 h at room temperaturein fue same
buffer containing 1 nM [3H]-YM-0915l-2 (86 Ci/rnmol).
8-0H-DPAT (50 nM) was added in each case to mask
possible binding of the ligands to serotonergic5-HT1a
sites. Non-specific binding was determined on adjacent
brillo sections by adding 1 ¡LM (+ )-butaclamol in the
buffer. Incubationswere terminatedby dipping fue slides
in ice-cold buffer followed by two consecutive 10 min
washesin fue samebuffer. After a final dipping in ice-cold
distilled water, slides were dried at room temperatureand
apposedto [3H]-Hyperfilm for 12 days, along side microscalescalibratedtritium standards.
The films from autoradiographyassayswere analyzed
using a computerized image analysis system (MCID-3,
Imaging Research,Ste-Catherine,Ontario). The binding
25
data were anaIyzedin brain regions accordingto Paxinos
and Watson[26], namely,caudate-putamen
(Cpu), nucleus
accumbens(NA), entopeduncularnucleus (EPN), external
segment of the globus pallidus (GPe), substantia nigra
(SN), substantianigra pars compacta (SNc) and ventral
pallidus (VP), expressedas fmol/mg wet tissue.Data were
comparedby a two-way ANOVA for two factors: strains
groups (Taiep and SD strainsrats) and age, followed by a
post-hocNewman-Keuls;P<O.O5being consideredsignificanto
Ketanserin,butaclamoland 8-0H-DPAT were purchased
from Sigma (St. Louis, MO). rH]-SCH23390 and [3H]YM-O9151-2 were obtained from DuPont NEN (Boston,
MA). [3H]-Hyperfilm, and microscale tritium standards
were purchasedfrom Amersham PharmaciaBiotch (Piscataway, NI). 2-Methyl-butane was from Aldrich (Nilwaukee,WI). EDTA, Gelatin and bovine serum albumin
were from Sigma (St. Louis, MO). All others chemicaI
used were of anaIyticaI reagent grade quality and were
obtainedfrom commerciaIsources.
3. Results
Dopamine Dl-like receptors as measured by [3H]SCH23390 binding were regían by regían compared
between fue SD and Taiep rats strains at two different
ages.Receptorlevels and its distribution were similar to
previous reports [12-14]. The highest specific labeling of
receptor was observed in caudate-putamennucleus, followed by fue nucleus accumbens,olfactory tubercle and
substantia nigra, whereas fue external segment of the
globus pallidus showedthe lowest level (Table 1 and Fig.
1). Comparisonsbetweenagesand strainsshowedthat DA
Dllevels in fue caudate-putamen
(Cpu); fue entopeduncular nuclei (EPN) and substantianigra (SN) regions were
significantly affectedby fue strain type (F¡.20=22.64,P=
0.0001 for Cpu; F¡.2o=18.4S,P=O.OO04,for EPN, and
F¡.20=42.90,P<O.OOOIfor SN, respectively) (Table 1).
Age factor did not show to affect receptor levels in all
theseregions(Table 1). Likewise, no evidenceof strainsX
age interaction was found in fue three regions (Table 1).
Similar results were observedfor the external segmentof
fue globus pallidus (F¡.2o=II.79, P=0.OO26) (Table 1).
Contrastingto that observedin the latter regions,dopamine
DI receptorslevels were not affectedby strain or age and
strainX age interaction in fue limbic subregions(Table 1).
Post-hoctest revealedthat 3-month-oldTaiep rats had a
significantly higher DI receptorslevels in the substantia
nigra (P<O.OI), entopeduncularnucleus (P<O.OS) and
external segmentof the globus pallidus (P<O.OS)with a
trend (P=0.06) in fue caudate-putamen
than SD rats at the
same age (Table 1 and Fig. 1). Dopamine DI receptors
levels in fue 9-month-oldgroupsrats were relatively alike.
Basal ganglia subregionsof fue Taiep rats showed significantly higher DI receptors levels in the caudateputamennucleus(P<O.OOI),entopeduncularnucleus(P<
26
G. Flores et al. I Brain Research956 (2002)24-29
Table 1
Quantitative evaluation oí Dl-like receptors by autoradiographyin
subregionsoí fue basal ganglia and limbic system
Dl-like
['H]-SCH-23390
% of Change
Sprague-Dawley
Taiep
(n=6)
(n=6)
236:t4
235:t8
43:t5
91:t13
140:t5
224:t 15
241:t15
270:t4
256:t12
79:t4*
150:t23*
166:t5
278:t9**
265:t13
114
109
184
165
118
124
110
199:t17
204:t17
42:t 10
78:t 13
126:t16
185:t11
218:t 16
262:t10**
242:t14
6O:t 10
162:t16**
145:t8
282:t 10**
239:t10
132
119
143
208
115
152
110
3 months old
Caudate-putamen
Nucleus accumbens
GPe
Entopeduncular nuclei
Ventral pallidus
SNr
Olfactory tubercle
9 months old
Caudate-putamen
Nucleus accumbens
GPe
Entopeduncular nuclei
Ventral pallidus
SNr
Olfactory tubercle
Receptor levels are expressed in fmol/mg of wet tissue and represent fue
mean:!:S.E.M. of pooled values obtained from four sections per animal.
Regions are defined according to Paxinos and Watson Atlas [20]. GPe,
external segment of fue globus pallidus; SNr, substantia nigra pars
reticulata. * P<0.05; ** P<O.OI compared with age-matched control
group.
0.01), substantianigra (P<O.OOl), with a trend (P=0.08)
in globus pal1idusexternal than SD rats of fue same age
(Table 1 and Fig. 1).
The DA DI receptors levels in the limbic subregions
including nucleus accumbens,olfactory tubercle and ventral pallidus were not affected by fue genetic background
of fue rats at both age groups.
3
[ H]-YM-09151-2 labels DA receptor subtypesbelonging to fue D2 family (D2, D3, and D4). Levels and
distribution obtained were similar to previous reports
[12,13]. The highest labeling was observed in caudateputamennucleus,followed by fue nucleusaccumbensand
olfactory tubercle with lower level in the substantianigra
pars compacta(Table 2). Comparisonsbetweenagesand
strainsshowedthat DA D2 levels in fue caudate-putamen,
nucleusaccumbens,olfactory tubercleand substantianigra
pars compactawere not significantly affected by strain or
age factors. Additionally, there was not significant
strainsX age interaction. Therefore, fue distribution and
density of D2-like binding sites did not differ significantly
betweenfuesetwo strainsof rats (SD and Taiep) compared
at two different ages(Table 2).
4. Discussion
In fue present study, we found that Taiep rats have
SD (3 months)
Taiep (3 months)
SD (9 montbs)
Taiep (9 montbs)
Fig. 1. Photomicrograph of D1-1ike receptor binding in fue brains of Taiep and Sprague-Daw1ey rats. Sagitta1 sections were incubated, as described in
Material and methods, in presence of 1 nM [3H]-SCH-23390. Resu1ts from fue quantitative ana1ysis of autoradiographic D1-1ike receptors binding are
presented in Tab1e 1. CPu, caudate-putamen; EP, entopeduncu1ar nuc1eus; GPe, externa1 segment of fue globus pa11idus; NA, nuc1eus'á!!6nmbens; OT,
olfactory tuberc1e; SNr, substantia nigra pars reticu1ata; VP. ventral pa11idum.
';",;
G. Flores et al.
Brain Research 956 (2002) 24-29
3 months old
Caudate-putamen
Nucleus accumbens
SNc
Olfactory tubercle
lO9:t6
89:t6
35:t4
74:tll
124:t2
lOO:t8
87:t8
26:t3
72:t7
IO8:t5
9O:t5
32:t8
72:t7
114
101
91
97
9 months old
Caudate-putamen
Nucleus accumbens
SNc
Olfactory tubercle
83:t8
25:t4
90:t5
108
95
96
125
higher levels of DA DI receptorsin basal ganglia subregions such as caudate-putamen,substantianigra pars reticulata, entopeduncularnuclei and externalsegmentof the
globos pallidus than wild SD rats and that changeswere
higher at 9 monthsold. DA DI receptorslevels in caudateputamen,substantianigra pars reticulataand entopeduncular nuclei revealed fue DA activity in the basal ganglia,
becausethose receptors are post-synaptic. In addition,
there were no differencesbetweenTaiep and SD rats in
terms of levels of DA DI receptorsin the limbic subregions. DA D2 receptorslevels were not different between
Taiep and SD rats at any time point. These findings are
consistentwith previous results indicating that Taiep rats
have altered DA function in the nigro-striatal DA system
comparedwith SD rats [35,36]. Furthermore,differences
in fue receptorslevels would imply differencesin genetic
elementsregulating the receptor expressionand therefore
explaindifferencesin fue motor disturbancesrelatedto DA
activity such as tremor and tonic immobility.
A number of evidences suggests that dopaminergic
neurons in the substantianigra pars compacta(SNc) as
well as some of their projecting regions, particularly fue
caudate-putamen,are critical in fue control of fue
locomotor activity. Dopaminergic drugs when applied
directly into fue basal ganglia subregions[6] as well as
neurochemicallesions of this pathway can producemotor
disorders such as Parkinsonism[6]. In addition, genetic
factors have been shown to playa critical role in fue
expression of the dopaminergic activity. The study of
geneticanimals modelshasallowed us to betterunderstand
the genetic contributions to dopaminergic disorders
[4,13,28]. However, there are some issues that remain
unclear. For example,changesin the nigro-striatal dopa-
minergic pathwayin Taiep rats mar be explainedeither to
genetic susceptibility or as result of abnonnal changes
occurring in other brain regions such as dysmyelination
[5,9,21,24]. In this regard, our findings mar be relevant
since we have found that Taiep rats exhibited highest
levels of DA DI receptor in fue basal ganglia subregions
compared with wild SD rats. In addition to fue typical
neurologicalsyndrome,Taiep rats show somesignsrelated
to fue narcolepsy-catalepsydisorder [27]. Therefore,DA
DI receptorslevels reportedhere mar, in part, playa role
in the development of the neurological syndrome that
characterizesto Taiep rats. In addition, our autoradiographic datasuggeststhat Taiep rats exhibited an increasein
the level of DA DI receptorsin the basalganglia,however
this increasemar be due to an enhancein the density or
affinity of this receptor.
The mechanism(s)by which Taiep rat develops an
increasein the level of DI receptorsin the basal ganglia
regions is not clear reto The changesin fue receptorlevels
describedin this study mar be explainedas a consequence
of a myelin loss or related to neurodevelopmentaldisturbances occurring in other brain regions (possibly fue
cerebellum) and secondary to an early dysmyelination.
This hypothesishas been proposed to explain the signs
observed in this mutant animal [5]. Another possible
explanation is that changesin DI binding in the Taiep
animalscould, in part, be resufting from reorganizationof
fue bared axon membranewith display higher density of
sodium channelspresentedin some chronically demyelinatedaxons[11,15]. In addition, it hasbeenrecentlyfound
that fue Taiep rat shows an increase in the SNS/PN3
sodium channel in cerebellar Purkinje cells following
myelin loss [2] with a progressivereactive astrocytosisin
the diencephalicstructuressuchas the striatum [20]. In fue
line with this suggestion, the progressive reactive astrocytosis in fue striatum mar in part be associatedwith
the progressive increase in fue dopamine DI receptors
reported here. Therefore, these changesmar be participated with fue functional alterations in those structures
involved in the motor control.
At cellular level, dysmyelination is associatedwith
increasedoligodendrocytesdeath [30] and the paucity of
fully mature oligodendrocytesis a major causeof myeline
deficiency [30]. Similarly, it has been describedthat the
myelination defect found in fue Taiep rat is due to an
abnonnal link of microtubules with smooth endoplasmic
reticulum membrane [5] thus leading to microtubule
accumulation in the oligodendrocyte cytoplasm [9,21].
However, our results suggestthat other mechanismsand
systems mar in part be involved as well. In fact, the
activation of fue glutamate receptors in the caudateputamen produce an up-regulation of dopamine DI receptors [31]. Furthennore,fue excessiveactivation of the
glutamate receptors expressedby oligodendrocytesmar
produce a massive oligodendrocyte death [22]. It is
unknown whether there are common mechanismbetween
28
G. Flores et al.
Brain Research 956 (2{)()2) 24-29
oligodendrocytesdeath and increase in fue DA DI receptorsin basal ganglia.
At behavioral level, it is clear that Taiep rat develops
tremor, ataxia,immobility episodes,epilepsyand paralysis
[19]. The apparentincreasein fue musculartalle suggested
by fue presenceof immobility episodeand tremor in the
Taiep rat may in part be correlatedwith fue increaselevel
of fue DA DI receptorsin fue basalganglia,becauserecent
studieshave suggeststhat DA DI receptorsare involved in
the regulation of musculartalle [17,18,32]. Sirnilarly, DA
DI receptors levels are also increased in fue caudateputamen from dystonia musculorum mutant rnice, an
animal model useto study fue humancerebellarataxia [1].
However, fue role to play the DA DI receptors in the
ataxia is not clear at this time. The traditional anticonvulsant action of dopamine has been attributed to DA D2
agonist in fue forebrain and the DA DI antagonistin the
rnidbrain [34]. Furthermore,behavioral [7,8] and electrophysiological [3,34] studies suggestthe participation of
DA DI receptorsin fue pathophysiologyof fue epilepsy
[3,7,8,34].Inhibition of fue substantianigra pars reticulata
(SNpr) has been shown suppress seizures in different
animal models of epilepsy [8]. While local application of
DA DI receptorligands increasesglutamatereleasein fue
SNpr [29]. Taken together, fuese data indicate that fue
increasedlevels of DA DI receptorsin the SNpr of the
Taiep rat may be participated in fue stimulation via
glutamate of this nucleus. However, further studies are
necessaryto correlatefue DA DI receptorslevels with fue
epilepsy episodes.
In summary, this study describedfurther characterizations of inherentstrain differencesthat exist betweenTaiep
and SD rats with respectto fue nigro-striatal DA system.
These results evidence that strain differences in DA
receptors are complex. However, fue development of
myelin disorderobservedin this mutantrat may, in part, be
mediatedby differencesin fue levels of DA DI receptors
in fue basal ganglia subregions.
[2]
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Acknowledgements
This study was supported in part by grants from
FundaciónMexicana para la Salud AC and fue Consejo
Nacional de Ciencia y Tecnologia,México (No. 30675-M
to q. Flores).We thank Juan J. Ramirezfor correctingthe
manuscript.J. Flores is a masterdegreestudent.G. Flo~es
and R. Mena are members of fue National System of
Researchersfrom Mexico.
[16]
[17]
[18]
[19]
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