 |
 Previous Article | Next Article 
The Journal of Neuroscience, June 15, 1998, 18(12):4732-4743
Plasticity of Synapses in the Rat Neostriatum after Unilateral
Lesion of the Nigrostriatal Dopaminergic Pathway
C. A.
Ingham,
S. H.
Hood,
P.
Taggart, and
G. W.
Arbuthnott
University of Edinburgh Centre for Neuroscience and Department of
Preclinical Veterinary Sciences, University of Edinburgh, Summerhall,
Edinburgh, United Kingdom EH9 1QH
 |
ABSTRACT |
In the 6-hydroxydopamine model of Parkinson's disease in the rat,
there is a significant reduction in the number of dendritic spines on
the principal projection neurons in the neostriatum, presumably
attributable to loss of the nigrostriatal dopamine input. These spines
invariably receive input from terminals forming asymmetric synapses
that originate mainly from the cortex. The object of the present study
was to determine the fate of those terminals after the loss of
dendritic spines. Unbiased estimates of synaptic density and absolute
numbers of synapses in a defined volume of the neostriatum were made
using the "disector" and Cavalieri techniques.
Numerical synaptic density of asymmetric synaptic contacts was 17%
lower in the neostriatum deprived of dopamine innervation and, in
absolute terms, there were 3 billion (19%) fewer contacts. The
numerical density of a subpopulation of asymmetric contacts on
dendritic spines that have complex or perforated synaptic
specializations and normally make up 9% of the asymmetric population
was 44% higher on the experimental side. Asymmetric synapses were
found to be enriched in glutamate using postembedding immunogold
labeling.
The present observations demonstrate that the loss of spines previously
reported after 6-hydroxydopamine lesions is accompanied by a loss of
asymmetric synapses rather than by the movement of synapses from spines
to other postsynaptic targets. The study also demonstrates that there
is an increase in complex synaptic interactions that have been
implicated in synaptic plasticity in other regions of the CNS after
experimental manipulations.
Key words:
Parkinson's disease; 6-hydroxydopamine; neostriatum; nigrostriatal pathway; corticostriatal pathway; plasticity; caudate; putamen; spines; perforated synapses
| |
INTRODUCTION |
The main synaptic input to dendritic
spines in the neostriatum is excitatory and is derived from the cortex
and thalamus. The synaptic contacts are on the heads of spines, they
are large with asymmetric membrane specializations, and they sometimes
have complex shapes (Kemp and Powell, 1971a ; Somogyi et al., 1981; Meshul and Casey, 1989; Chen and Hillman, 1990). A proportion of spines
also receive a second synaptic input, which usually has small symmetric
membrane specializations, and a high proportion of them have been
proposed to be dopaminergic (Freund et al., 1984).
Parkinson's disease is characterized by the loss of dopaminergic
neurons in the substantia nigra pars compacta, which normally provide
dopaminergic input to the caudate nucleus and putamen (neostriatum). A
well characterized animal model of Parkinson's disease is the
unilateral destruction of the dopaminergic pathway in rats by
administration of 6-hydroxydopamine (6-OHDA) (Ungerstedt and
Arbuthnott, 1970). In this model morphological changes have been
observed in the neostriatum, including a 12-19% decrease in the
density of dendritic spines on the most common type of neostriatal
neuron, the medium-sized spiny neuron (Ingham et al., 1989, 1993). This
decrease in density of dendritic spines is assumed to be a response to
the loss of the dopaminergic input to the spines. This finding raises
the question of the fate of excitatory terminals that form asymmetrical
synapses at the head of the spines. There are two possibilities: (1)
terminals may move to an alternative postsynaptic target; or (2) they
may degenerate. The object of the present study is to test these
possibilities using unbiased design-based stereological methods
(Sterio, 1984; Coggeshall, 1992) to estimate the numerical density and
absolute numbers of asymmetric synaptic contacts in the neostriatum
after unilateral 6-OHDA lesions.
| |
MATERIALS AND METHODS |
6-Hydroxydopamine lesion and behavioral testing
Adult male Wistar rats (200-250 gm; Charles River Laboratories,
Margate, UK) were used in this study. Housing conditions and all
procedures that were performed on them were in accordance with the
Animals Act of 1986 for scientific procedures and were in accordance
with the policy on the use of animals in neuroscience research issued
by the Society for Neuroscience. The dopaminergic nigrostriatal pathway
was unilaterally destroyed as described previously (Ingham et al.,
1993) in seven rats. Thirty minutes after treatment with pargyline (50 mg/kg in saline, i.p.; Sigma, Poole, UK) and desmethylimipramine (25 mg/kg in saline, i.p.; Sigma), the rats were anesthetized with
halothane in air (1-2%) and injected with 2 µl of saline containing
6 µg 6-OHDA (Sigma) and 0.4 µl of ascorbic acid into the left
medial forebrain bundle. The stereotaxic coordinates were as follows:
anteroposterior, 5.2 mm anterior of the interaural line; lateral, 1.7 mm lateral of bregma; and ventral, 8.2 mm ventral to the brain surface.
The success of the lesion was tested (Ungerstedt and Arbuthnott, 1970) 9 or 10 d after the operation by determining the number of turns the animals make in response to the administration of apomorphine (0.25 mg/kg in H20, i.p.; Research Biochemicals, St Albans, UK). Those animals that turned >200 complete circles away from the injected
side in 45 min were used for further study and were considered to have
at least 90% loss of dopamine from the lesioned side (Hefti et al.,
1980).
Tissue preparation
Twenty-six days after the lesion the rats were anesthetized with
sodium pentobarbitone (60 mg/kg, i.p.) and perfused through the aorta
with calcium-free Tyrodes solution at 37°C for 30 sec followed by 500 ml of warm fixative at 37°C for 5 min and 700 ml of cold fixative at
4°C for 20 min. The fixative consisted of 2% paraformaldehyde and
2.5% glutaraldehyde in 0.1 M sodium phosphate buffer, pH
7.4 (PB). Coronal sections of 70 µm were cut on a vibrating microtome
(Vibratome, Lancer) in PB. Sections were collected from the level at
which the corpus callosum first crosses the midline (10.6 mm anterior
of the interaural line) to where the fornix joins the diencephalon (8.2 mm anterior of the interaural position) (Paxinos and Watson, 1982).
Every third section was taken for analysis; however, the choice of
whether the first, second, or third section cut was used was determined at random so that the volume of the neostriatum could be estimated using the Cavalieri method (Coggeshall, 1992). The sections were washed
in PB, treated with 1% osmium tetroxide in PB for 40 min, dehydrated,
embedded in resin, and mounted on microscope slides (Ingham et al.,
1993).
Quantitative analysis
The Cavalieri method for estimating the volume
(Vref). The sections through the
neostriatum were digitized by placing the slides on a light box and
viewing them with a macro lens attached to a video camera. The area of
the neostriatum on each side of every section was measured (using NIH
Image software) and then the following formula was applied:
|
(1)
|
where a is the mean area of neostriatum, t
is the thickness of the vibratome sections (70 µm), and s
is the total number of sections through the defined region of
neostriatum (usually 30).
A specified region of the neostriatum was considered, which could be
easily defined with unambiguous anatomical boundaries. The anterior and
posterior boundaries have been described above. The corpus callosum
defines the dorsal and lateral boundaries, the lateral ventricle
defines the medial edge, and an arbitrary ventral boundary consisted of
a line drawn from the ventral tip of the lateral ventricle to the
rhinal fissure. The globus pallidus was excluded from this defined
region in sections in which the imaginary line crossed its borders
(Fig. 1).
View larger version (18K):
[in this window]
[in a new window]
|
Figure 1.
Drawings of coronal sections through the rat brain
(Paxinos and Watson, 1982) showing the region of neostriatum considered
in the present study (shaded area). The anterior limit
was taken as the place in which the corpus callosum crosses the
midline, and the caudal limit was the place in which the fornix joins
the diencephalon. The dorsal limit was the corpus callosum, and the
ventral limit was an imaginary line drawn from the bottom of the
lateral ventricle to the rhinal fissure. The black boxes
show where samples were taken for estimation of synaptic density. The
same region on each side of individual animals was compared.
|
|
Electron microscopic sampling. Regions from three sections
(chosen by systematic random sampling) through the experimental and
contralateral neostriata of each animal were selected randomly by
dropping a square card (1 cm2) from 15 cm above the
appropriate figure of the rat atlas (Paxinos and Watson, 1982) (Fig. 1)
and accepting it if it fell within the neostriatum. The same region on
both sides of the brain was excised and reembedded as described
previously (Bolam, 1992), giving a total of 42 blocks. Serial sections
(silver) were cut (~10 per grid) and collected on Formvar-coated
copper slot grids, stained with lead citrate, and examined in a Philips
400 electron microscope (EM). The disector analysis of each block was
performed on 15 pairs of electron micrographs (final magnification,
25,000×) from two adjacent sections of a similar thickness (Hunter and Stewart, 1993). A systematic random-sampling method was used whereby each micrograph was taken at least two widths of the EM screen apart.
All structures were included in the sampling method, i.e., groups of
myelinated fibers, cell somata, and blood capillaries. Regions obscured
in some way, e.g., with folds or contamination were avoided. Each pair
of electron micrographs represent two disectors with micrograph 1 acting as the reference section and micrograph 2 as the "look up"
section and vice versa (Figs.
2, 3).
View larger version (198K):
[in this window]
[in a new window]
View larger version (198K):
[in this window]
[in a new window]
|
Figure 2.
A pair of electron micrographs taken from serial
sections through the neostriatum (contralateral side). Synapses that
were within the unbiased counting frame are labeled. Synaptic contacts
are labeled according to their membrane specialization
(a, asymmetric; s, symmetric) and their
postsynaptic targets (sp, spine; d,
dendrite; ?, unknown). Stars mark tops of
synapses, i.e., those found in the reference but not the look up
section. Asterisks mark presynaptic boutons that make
synapses with two different postsynaptic targets. Each micrograph was
used as the reference and as the look up with its matching pair. Scale
bar, 1 µm.
|
|
View larger version (196K):
[in this window]
[in a new window]
View larger version (196K):
[in this window]
[in a new window]
|
Figure 3.
A pair of electron micrographs taken from serial
sections through the neostriatum (experimental side). Synapses that did
not cross the forbidden lines of the the unbiased counting frame are
labeled. Synaptic contacts are labeled according to their membrane
specialization (a, asymmetric; s,
symmetric) and their postsynaptic targets (sp, spine;
d, dendrite; ?, unknown).
Stars mark tops of synapses, i.e., those found in the
reference but not the look up section. Asterisks mark
presynaptic boutons that make synapses with two different postsynaptic
targets. Arrowheads mark the discontinuities of complex
synaptic contacts. Each micrograph was used as the reference and as the
look up with its matching pair. Scale bar, 1 µm.
|
|
Identification of synapses
Synapses were recognized on the micrographs by the accumulation
of at least three synaptic vesicles at the presynaptic site, a widened
synaptic cleft with parallel presynaptic and postsynaptic membranes,
and a thickened postsynaptic membrane (Figs. 2, 3). Asymmetric synapses
possessed a marked postsynaptic density, whereas symmetric synapses
only had a slight thickening adjoining the membrane. The synapses and
their associated postsynaptic targets were identified as
asymmetric-soma, asymmetric-dendrite, asymmetric-spine, or
asymmetric-? (when it was not possible to unequivocally identify the
postsynaptic target). Symmetric synapses were classified in the same
way. Complex or perforated synaptic contacts, defined by discontinuous
specializations, were identified as were boutons in synaptic contact
with more than one postsynaptic target. Spines with two asymmetric
contacts from different boutons were also noted. A rectangular unbiased
counting frame (44.58 µm2) (Gundersen, 1977) was
placed over the micrographs, and the parameters outlined below were
recorded on a spreadsheet (Microsoft Excell).
Estimation of mean synaptic numerical density
(Nv syn)
Synaptic number per cubic micrometer was calculated using the
formula:
|
(2)
|
adapted from Sterio (1984) and De Groot and Bierman
(1986), where: Q syn are synapses present in the reference
section but not the look up section (referred to as "tops");
h is distance between disector planes (i.e., section
thickness), and A is sample area.
Estimation of absolute numbers of synapses (N)
|
(3)
|
Estimation of section thickness
Section thickness was determined using the minimal fold method.
At least three suitable folds were located on the sections used and
photographed at a magnification of 70,000×. Section thickness was
estimated to be half of the mean width of the measured folds (Small,
1968).
Postembedding immunogold labeling
Sections from a pair of samples taken from one animal were
processed at the same time for postembedding immunogold labeling using
an antiserum to glutamate and a variation of the immunogold procedure
used previously (Phend et al., 1992). In brief, serial sections (gold
interference color) were cut (~10 per grid), collected on
Formvar-coated gold slot grids, and rinsed three times for 10 min each
in 0.05 M Tris-PBS containing 0.01% Triton X-100 (TPBS-TX) before incubation in primary antiserum. All incubations and rinses were
performed at room temperature. The anti-L-glutamate serum (code 03) was kindly provided by Drs O. P. Ottersen and J. Storm-Mathisen and was used at a dilution of 1:500. Properties of
this antiserum have been described previously, including that it
recognizes glutamate fixed to protein with glutaraldehyde (Ottersen and
Storm-Mathisen, 1984). The antiserum weakly cross-reacts with glutamine
and aspartate, but this is abolished after preincubation of the
antiserum with 100 µM glutaraldehyde conjugates of these
amino acids (Maxwell et al., 1992). This procedure was therefore
performed. The primary antiserum was diluted with TPBS-TX containing
1% normal goat serum, and sections were incubated for ~18 hr.
Further washes in TPBS-TX were followed by incubation in anti-rabbit
IgG coupled to 15 nm colloidal gold at a dilution of 1:10 in TPBS-TX
for 2 hr. Finally, after washing, the grids were stained with 1%
aqueous uranyl acetate for 15 min and lead citrate for 2.5 min
(Reynolds, 1963), and they were examined in a Philips 400 EM.
A systematic random-sampling method was used to collect 15 electron
micrographs from a single section (final magnification, 25,000×)
whereby each micrograph was taken at least two widths of the EM screen
apart. The electron micrograph negatives were digitized at a resolution
of 500 dots per inch using a UC 1200S scanner (Umax Data Systems Inc.).
The density of gold particles and the cross-sectional areas were
calculated for all asymmetric-spinous synaptic boutons, all symmetric
synaptic boutons, and all postsynaptic structures to these synapses.
Gold particle density was also calculated over the lumen of any blood
capillaries present. The calculations were made using a grain counting
program (Newgrains) written for the purpose on a Sun SPARCstation 20 Unix workstation (Ingham et al., 1997). Statistical comparisons were
made (Statview II, Apple Macintosh) using unpaired Student's
t tests and one-way ANOVA with post hoc means
tests.
| |
RESULTS |
Ninety disectors (30 from each of three blocks) were analyzed from
each contralateral and experimental neostriatum from seven animals
(total of 1260 disectors). Asymmetric contacts accounted for 77-80%
of synapses, whereas symmetric contacts accounted for only 20-23%.
Boutons making asymmetric contacts generally contained small spherical
clear vesicles, and their postsynaptic targets were usually dendritic
spines or structures that could not be unequivocally identified (Table
1). Dendritic shafts were also occasionally contacted, whereas cell bodies were not (Table 1). Boutons
making symmetrical contacts had pleomorphic synaptic vesicles ranging
from small and elongated to large and round; postsynaptic targets
included cell bodies, dendritic shafts, and spines (Figs. 2, 3, Table
1).
View this table:
[in this window]
[in a new window]
|
Table 1.
Distribution of different postsynaptic targets to
asymmetric and symmetric synapses in the contralateral and experimental
neostriata of rats (n = 7) lesioned with 6-OHDA
|
|
The numbers of asymmetric contact tops, i.e., those found in the
reference but not the look up section, ranged from 143 to 240 on each
side of each animal in a defined volume that ranged from 199 to 247 µm3. The numbers of symmetric contact tops ranged
from 30 to 61 in the same volume. The estimated numerical density of
asymmetric contacts was significantly lower in the neostriatum on the
experimental side (mean reduction of 17%; paired Student's
t test, p < 0.05; Table
2). The volume of neostriatum calculated
using the Cavalieri method (Eq. 1) ranged from 14.8 to 19.2 µm3. The absolute number of synapses
(N) in the specified region of neostriatum was
estimated for each side of each animal (Eq. 3), and the number of
asymmetric synapses was found to be significantly smaller (mean
reduction of 19%; paired Student's t test,
p < 0.05; Table 2) on the experimental side.
View this table:
[in this window]
[in a new window]
|
Table 2.
Mean density and absolute numbers of asymmetric and
symmetric synapses (± SD) in the contralateral and experimental
neostriata of rats (n = 7) lesioned with 6-OHDA
|
|
The mean numerical density estimate of complex or perforated synapses
in the experimental neostriatum was significantly higher (0.11 ± 0.02 SD) when compared with that on the contralateral side (0.08 ± 0.02 SD; paired Student's t test, p < 0.05; Figs. 4, 5C,D). Complex synapses formed an average of
9% of the total asymmetric synapse population on the contralateral
side and 15% of them on the experimental side of the brain. The
density of asymmetric synapses onto unidentified targets
(asymmetric-?) was significantly lower (paired Student's t
test, p < 0.05; Fig.
4) on the
experimental side (24%; Fig. 4). Similarly, absolute numbers of
asymmetric synapses onto spines and those onto unidentified targets
(asymmetric-?) were significantly lower on the experimental side
(spines, 20% lower; unidentified targets, 27% lower; Fig. 4).
View larger version (1K):
[in this window]
[in a new window]
|
Figure 4.
Mean estimates of the numerical synaptic density
and the absolute number of synapses in the specified region of
neostriatum from the contralateral and experimental sides of 6-OHDA
lesioned rats (n = 7, mean ± SE). The results
are subdivided according to the membrane specialization of synaptic
contacts (A, as, asymmetric;
B, s, symmetric) and according to their
postsynaptic targets (sp, spine; den,
dendrite; ?, unknown). C, Subpopulations
of synapses with discontinuous (complex) synaptic
contacts, with more than one postsynaptic target (ps
target > 1) and a subpopulation of spines receiving two
asymmetric synapses (sp > 1as).
Asterisks show a significant difference when estimates
from the contralateral and experimental sides are compared
(paired Student's t test, p < 0.05).
|
|
View larger version (181K):
[in this window]
[in a new window]
|
Figure 5.
A, B, Pair of electron micrographs
taken from serial sections through the neostriatum (contralateral side)
that have been immunogold labeled using an antiserum to glutamate. Gold
particles are enriched in vesicle-containing boutons that make
asymmetric synaptic contacts (four of which are numbered
1-4 in A,
B) with spines (sp) or unidentified targets
(?). Symmetric synapses
(arrowheads) and postsynaptic targets (sp,
?) are not enriched in gold particles. C, D,
Electron micrographs of spines (sp) and their synaptic
input taken from the rat neostriatum on the experimental side. Boutons
with small round vesicles make obvious asymmetric synaptic contact with
spine heads (arrowheads). These contacts are sometimes
discontinuous and are therefore classified as complex
(arrows). Spines can be recognized by their spine
apparatus (asterisks). In C, a second
bouton with large pleomorphic vesicles makes symmetrical synaptic
contact with the head of the spine (curved arrow). Scale
bars: A, B, 0.5 µm; C, D, 0.3 µm.
|
|
Immunogold labeling using the
L-glutamate antiserum
Gold particles were distributed throughout the neostriatum, but
high densities were observed overlying populations of myelinated and
unmyelinated axons, preterminal vesicle-containing structures, and
boutons with small round vesicles and asymmetric synaptic specializations (Fig. 5A,B). In both the contralateral and
experimental neostriata, the mean density of gold particles over
boutons with asymmetric synaptic contacts on dendritic spines was
significantly greater than that over postsynaptic structures or boutons
with symmetric synaptic specializations (Table
3). Moreover, the gold particle density
over these asymmetric boutons was significantly greater on the
ipsilateral, dopamine-denervated neostriatum compared with that on the
contralateral side. Cross-sectional areas of asymmetric and symmetric
synaptic boutons and their postsynaptic targets in the neostriata were
not significantly different between the two sides of the brain.
View this table:
[in this window]
[in a new window]
|
Table 3.
Mean gold particle density (± SD) over different
structures in the contralateral and experimental neostriata of one rat
lesioned with 6-OHDA
|
|
| |
DISCUSSION |
The present study shows that there are 19% fewer asymmetric
synapses in the neostriatum that has been deprived of its dopaminergic input compared with the contralateral side where the dopaminergic input
is intact. The decrease is not attributable to the loss of the
dopaminergic synapses, because the results of studies using a variety
of approaches have revealed that dopaminergic terminals form
symmetrical synapses (Bouyer et al., 1984; Freund et al., 1984; Voorn
et al., 1986; Groves et al., 1994; Smith et al., 1994). This implies
that there is a secondary loss of nondopaminergic synapses after
removal of the nigrostriatal pathway. The loss of asymmetric synapses
is, remarkably, the same as the 19% decrease in dendritic spine
density found on medium-sized spiny neurons 26 d after a 6-OHDA
lesion (Ingham et al., 1989, 1993). Spines form the major postsynaptic
target of asymmetric synapses, which confirms previous findings in
control material (Kemp and Powell, 1971a). Although 20-23% of
postsynaptic targets were not unequivocally identified in the present
material, many of them will also be spines, which would increase the
percentage of these postsynaptic targets to 80-90%. The findings of
spine and synapse loss complement each other and are consistent with
the suggestion that loss of spines after a 6-OHDA lesion is accompanied
by a loss of asymmetric synapses on those spines. The population of
asymmetric synapses is likely to be of cortical origin (Kemp and
Powell, 1971b; Hattori et al., 1978; Somogyi et al., 1981; Bouyer et
al., 1984; Xu et al., 1989), although they may also include some
thalamostriatal terminals (Kemp and Powell, 1971b; Xu et al., 1991).
The enrichment of immunogold labeling in asymmetric boutons using an
antiserum to L-glutamate in the present study has also
confirmed the glutamatergic nature of the majority of asymmetric
synapses in the neostriatum (McGeer et al., 1977; Fonnum et al., 1981;
Ingham, 1992).
Effect of unilateral destruction of the nigrostriatal
dopamine pathway
Understanding the significance of a 19% loss of spines and
synapses after dopamine denervation depends on which spines and synapses disappear. There are at least three possibilities: first, spines and synapses may be lost from a specific neuronal subtype; second, there may be a specific origin of the presynaptic synapses that
are lost; and third, the loss of dopamine may have a generalized action
that is independent of presynaptic or postsynaptic origins of the lost
synapses. These will be considered in turn.
First, there are at least two subtypes of medium-sized spiny neurons in
the neostriatum that receive synaptic input from dopamine synapses
(Freund et al., 1984; Yung et al., 1996). One population of neurons
project "directly" to the substantia nigra pars reticulata and
colocalize the neuropeptides substance P and/or dynorphin with GABA,
whereas another population of neurons send their axons primarily to the
globus pallidus and colocalize the neuropeptide enkephalin with GABA
(Penny et al., 1986; Gerfen and Young, 1988). Dopamine denervation may
produce a differential response of these two populations, one becoming
more vulnerable to spine and synapse loss after the lesion. This
question is extremely important because an imbalance of activity in
these two pathways is thought to be critical in producing the
hyperkinesias or hypokinesias of basal ganglia disorders (Albin et al.,
1989; Alexander and Crutcher, 1990; DeLong, 1990).
Spine necks are the primary postsynaptic target of dopamine terminals
(Freund et al., 1984; Groves et al., 1994), and those spines that
previously received direct dopaminergic synapses onto their necks may
be specifically lost. The percentage of spines that receive dopamine
synapses is not known, although it has been shown in one identified
striatonigral neuron (i.e., directly projecting) that 39% of spines
(87 studied between 60 and 100 µm from the cell soma) receive both a
dopaminergic synapse and an asymmetric synapse (Freund et al., 1984).
However, in other studies, it can be estimated that <8% of spines
receive dopaminergic input (Wilson et al., 1983; Groves et al., 1994).
In the current study it is possible to relate the numbers of asymmetric
and symmetric synapses onto spinous postsynaptic targets and estimate
that 15% of dendritic spines receive both an asymmetric and symmetric
synapse in control neostriatum. However, it should be pointed out that
not all symmetric synapses will contain dopamine, and so our figures
are closer to the lower densities estimated in other studies (Wilson et
al., 1983; Groves et al., 1994). It is also important to note that the
estimates of symmetric synaptic densities in the current study may be
inaccurate because of the small numbers counted overall (Coggeshall,
1992). The combined data from the current and previous studies (Wilson
et al., 1983; Freund et al., 1984; Groves et al., 1994) suggest that
the percentage of spines that receive dopamine synapses is not
consistent and could differ depending on the projection site of the
output neuron, the chemical compartment (patch or matrix), or even on
the part of the dendrite examined.
The second possibility is that the source of the asymmetric synapses on
spine heads determines which synapses and spines are lost. Two
morphologically distinct corticostriatal pathways have been observed in
rats from both agranular cortex (Wilson, 1987) and sensory "barrel
cortex" (Wright et al., 1995). Moreover, ipsilateral- and
contralateral-projecting motor corticostriatal terminals may contact
different proportions of dendrites and spines as well as differing
proportions of D1 and D2 receptor protein-immunoreactive targets
(Hersch et al., 1995); see Hanley and Bolam (1997) for alternative
findings.
Finally, the loss of synapses and spines may be a random process. This
would imply that dopamine subserves a neurotrophic function and could
play a role in the maintenance of spines. Indeed, the
dopamine-containing cells have been shown to contain neurotrophins of
various classes, including BDNF and NT3 (Seroogy et al., 1994), and it
may be the release of these factors, rather than dopamine, that is
important for spine survival.
In contrast to the overall loss of asymmetric synapses, there was a
significant increase in the numerical density of a subpopulation of
asymmetric synapses. This subpopulation has complex, discontinuous synaptic specializations that may be perforated. These synapses normally make up ~9% of the asymmetric synaptic population, but this
increases by 44% so that 15% of asymmetric synaptic specializations are complex after dopamine denervation. The estimate of absolute number
was not significantly different; however, the small number of tops
counted in each analysis (10-30) could easily explain the inability to
detect a significant difference.
An increase in the proportion of perforated to nonperforated synapses
has been suggested to occur in the putamen of parkinsonian patients and
after dopamine receptor blockade in rats with haloperidol (Meshul et
al., 1992, 1994; Meshul and Tan, 1994; Anglade et al., 1996), although
unbiased methodology was not used in any of these studies. There is
evidence that synapses with complex or perforated postsynaptic
densities have increased efficacy, and they have been implicated in
synaptic remodeling in the hippocampus in which their numbers increase
with long-term potentiation (Calverley and Jones, 1990; Geinisman et
al., 1991; Lisman and Harris, 1993; Harris and Kater, 1994; Pierce and
Lewin, 1994). Loss of a specific population of asymmetric synapses and
an accompanying increase in a specific population of perforated
asymmetric synapses could have very important functional consequences
that may play a major role in the development of Parkinson's disease.
It is not known whether complex synaptic specializations in the
neostriatum have a specific source or postsynaptic target. This is of
key importance, because an increase of complex synaptic specializations
on the neurons that project indirectly to the substantia nigra via the globus pallidus could explain the increased activity in this pathway and the results suggesting an overactivity in the corticostriatal pathway after dopamine denervation (Lindefors and Ungerstedt, 1990;
Greenamyre and O'Brien, 1991). The link between overactivity in a
corticostriatal projection and the striatopallidal pathway is also
consistent with results showing a reversal of changes in
preproenkephalin mRNA levels after cortical lesions (Campbell and
Björklund, 1994) or blockage of NMDA receptors (Hajji et al.,
1996).
Suggestions of glutamate hyperactivity in Parkinson's disease have
been addressed in animal models, and joint treatment with low doses of
NMDA antagonists markedly potentiates the therapeutic effects of
dopaminergic agonists (Greenamyre and O'Brien, 1991; Starr, 1995;
Blandini et al., 1996). Suggested anatomical locations for this action
have included the subthalamic nucleus, the substantia nigra, and the
neostriatum. There is preliminary evidence for a striatal location,
because structural alterations in the neostriatum after neuroleptic
treatment were reversed by NMDA antagonists (Meshul et al., 1994). The
present study also showed increased immunogold labeling indicating an
increased concentration of glutamate (Ottersen, 1989) in asymmetric
synaptic boutons, which could be a further indication of hyperactivity
in the remaining boutons. This finding however, needs confirmation.
Symmetric synapses
The estimated numerical density and absolute number of symmetric
synapses were not significantly lower in the experimental neostriatum.
Symmetric synapses formed ~20% of the total synaptic population in
the contralateral neostriatum. Dopaminergic boutons probably make up
~9% of the total number of synapses and always make symmetrical
synaptic contacts (Freund et al., 1984; Groves et al., 1994); see
Hattori et al. (1991) for an alternative view. It is surprising that a
9% decrease in symmetric synapses was not detected in the present
study. There are at least three explanations for this: (1) the small
number of symmetric synapse tops counted may not produce a reliable
estimate of their synaptic density (Coggeshall, 1992); (2) the smallest
symmetric synapses that are likely to include the dopaminergic
population are sometimes hard to identify and could therefore be
underestimated; and (3) there may have been compensatory sprouting of
other populations of nerve fibers. Morphological plasticity has been
shown to occur in enkephalin-immunoreactive axon collateral and
terminal boutons of medium-sized spiny neurons in the rat neostriatum
and globus pallidus after unilateral 6-OHDA lesion of the nigrostriatal
pathway (Ingham et al., 1991, 1997).
In summary, this study shows that corticostriatal (and/or
thalamostriatal) synapses are lost as a result of dopaminergic
denervation. If a similar loss occurs in Parkinson's disease, then it
could be contributing to the symptomology of the human disorder and could be specifically targeted in novel therapeutic strategies.
| |
FOOTNOTES |
Received Dec. 29, 1997; revised March 23, 1998; accepted March 26, 1998.
This study was supported by the Wellcome Trust, UK (Grant 040197). We
thank Drs. O. P. Ottersen and J. Storm-Mathisen for provision of
glutamate antiserum and Prof. J. P. Bolam for discussions throughout the study, especially during preparation of this manuscript. Correspondence should be addressed to Dr. C. A. Ingham, University of Edinburgh Centre for Neuroscience, R(D)SVS, Department of
Preclinical Veterinary Sciences, Summerhall, Edinburgh, EH9 1QH, UK.
| |
REFERENCES |
-
Albin RL,
Young AB,
Penney JB
(1989)
The functional anatomy of basal ganglia disorders.
Trends Neurosci
12:366-375[Web of Science][Medline].
-
Alexander GE,
Crutcher MD
(1990)
Functional architecture of basal ganglia circuits: neural substrates of parallel processing.
Trends Neurosci
13:266-271[Web of Science][Medline].
-
Anglade P,
Mouatt-Prigent A,
Agid Y,
Hirsch EC
(1996)
Synaptic plasticity in the caudate nucleus of patients with Parkinson's disease.
Neurodegeneration
5:121-128[Web of Science][Medline].
-
Blandini F,
Porter RHP,
Greenamyre JT
(1996)
Glutamate and Parkinson's disease.
Mol Neurobiol
12:73-94[Web of Science][Medline].
-
Bolam JP
(1992)
Preparation of central nervous system tissue for light and electron microscopy.
In: Experimental neuroanatomy: a practical approach (Rickwood D,
Hames BD,
eds), pp 1-29. New York: Oxford UP.
-
Bouyer JJ,
Park DH,
Joh TH,
Pickel VM
(1984)
Chemical and structural analysis of the relation between cortical inputs and tyrosine hydroxylase-containing terminals in rat neostriatum.
Brain Res
302:267-275[Web of Science][Medline].
-
Calverley RKS,
Jones DG
(1990)
Contributions of dendritic spines and perforated synapses to synaptic plasticity.
Brain Res Rev
15:215-249[Medline].
-
Campbell K,
Björklund A
(1994)
Prefrontal corticostriatal afferents maintain increased enkephalin gene expression in the dopamine-denervated rat striatum.
Eur J Neurosci
6:1371-1383[Web of Science][Medline].
-
Chen S,
Hillman DE
(1990)
Robust synaptic plasticity of striatal cells following partial deafferentation.
Brain Res
520:103-114[Web of Science][Medline].
-
Coggeshall RE
(1992)
A consideration of neural counting methods.
Trends Neurosci
15:9-13[Web of Science][Medline].
-
De Groot DMG,
Bierman EPB
(1986)
A critical evaluation of methods for estimating the numerical density of synapses.
J Neurosci Methods
18:79-101[Web of Science][Medline].
-
DeLong MR
(1990)
Primate models of movement disorders of basal ganglia origin.
Trends Neurosci
13:281-285[Web of Science][Medline].
-
Fonnum F,
Storm-Mathisen J,
Divac I
(1981)
Biochemical evidence for glutamate as neurotransmitter in corticostriatal and corticothalamic fibres in rat brain.
Neuroscience
6:863-873[Web of Science][Medline].
-
Freund TF,
Powell JF,
Smith AD
(1984)
Tyrosine hydroxylase-immunoreactive boutons in synaptic contact with identified striatonigral neurons, with particular reference to dendritic spines.
Neuroscience
13:1189-1215[Web of Science][Medline].
-
Geinisman Y,
de Toledo-Morrell L,
Morrell F
(1991)
Induction of long-term potentiation is associated with an increase in the number of axospinous synapses with segmented postsynaptic densities.
Brain Res
566:77-88[Web of Science][Medline].
-
Gerfen CR,
Young III WS
(1988)
Distribution of striatonigral and striatopallidal peptidergic neurons in both patch and matrix compartments: an in situ hybridization histochemistry and fluorescent retrograde tracing study.
Brain Res
460:161-167[Web of Science][Medline].
-
Greenamyre JT,
O'Brien CF
(1991)
N-Methyl-D-aspartate antagonists in the treatment of Parkinson's disease.
Arch Neurol
48:977-981[Abstract/Free Full Text].
-
Groves PM,
Linder JC,
Young SJ
(1994)
5-hydroxydopamine-labeled dopaminergic axons: three-dimensional reconstructions of axons, synapses and postsynaptic targets in rat neostriatum.
Neuroscience
58:593-604[Web of Science][Medline].
-
Gundersen HJG
(1977)
Notes on the estimation of the numerical density of arbitrary profiles: the edge effect.
J Microsc
111:219-223.
-
Hajji MD,
Salin P,
Kerkerian-Le Goff L
(1996)
Chronic dizocilpine maleate (MK- 801) treatment suppresses the effects of nigrostriatal dopamine deafferentation on enkephalin but not on substance P expression in the rat striatum.
Eur J Neurosci
8:917-926[Web of Science][Medline].
-
Hanley JJ,
Bolam JP
(1997)
Synaptology of the cortical projection to the ipsilateral and contralateral neostriatum of the rat: relation to the patch-matrix complex.
Brain Res Assoc Abstr
14:56.
-
Harris KM,
Kater SB
(1994)
Dendritic spines: Cellular specializations imparting both stability and flexibility to synaptic function.
Annu Rev Neurosci
17:341-371[Web of Science][Medline].
-
Hattori T,
McGeer EG,
McGeer PL
(1978)
Fine structural analysis of cortico-striatal pathway.
J Comp Neurol
185:347-354[Web of Science].
-
Hattori T,
Takada M,
Moriizumi T,
Van der Kooy D
(1991)
Single dopaminergic nigrostriatal neurons form two chemically distinct synaptic types: Possible transmitter segregation within neurons.
J Comp Neurol
309:391-401[Web of Science][Medline].
-
Hefti F,
Melamed E,
Wurtman RJ
(1980)
Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization.
Brain Res
195:123-137[Web of Science][Medline].
-
Hersch SM,
Ciliax BJ,
Gutekunst C-A,
Rees HD,
Heilman CJ,
Yung KKL,
Bolam JP,
Ince E,
Yi H,
Levey AI
(1995)
Electron microscopic analysis of D1 and D2 dopamine receptor proteins in the dorsal striatum and their synaptic relationships with motor corticostriatal afferents.
J Neurosci
15:5222-5237[Abstract].
-
Hunter A,
Stewart MG
(1993)
Long-term increases in the numerical density of synapses in the chick lobus parolfactorius after passive avoidance training.
Brain Res
605:251-255[Web of Science][Medline].
-
Ingham CA
(1992)
Immunocytochemistry II: post-embedding staining.
In: Experimental neuroanatomy: a practical approach (Bolam JP,
ed), pp 129-151. Oxford: Oxford UP.
-
Ingham CA,
Hood SH,
Arbuthnott GW
(1989)
Spine density on neostriatal neurons changes with 6-hydroxydopamine lesions and with age.
Brain Res
503:334-338[Web of Science][Medline].
-
Ingham CA,
Hood SH,
Arbuthnott GW
(1991)
A light and electron microscopical study of enkephalin-immunoreactive structures in the rat neostriatum after removal of the nigrostriatal dopaminergic pathway.
Neuroscience
42:715-730[Web of Science][Medline].
-
Ingham CA,
Hood SH,
Van Maldegem B,
Weenink A,
Arbuthnott GW
(1993)
Morphological changes in the rat neostriatum after unilateral 6- hydroxydopamine injections into the nigrostriatal pathway.
Exp Brain Res
93:17-27[Web of Science][Medline].
-
Ingham CA,
Hood SH,
Mijnster MJ,
Baldock RA,
Arbuthnott GW
(1997)
Plasticity of striatopallidal terminals following unilateral lesion of the dopaminergic nigrostriatal pathway: a morphological study.
Exp Brain Res
116:39-49[Web of Science][Medline].
-
Kemp JM,
Powell TPS
(1971a)
The synaptic organization of the caudate nucleus.
Philos Trans R Soc Lond B Biol Sci
262:403-412[Abstract/Free Full Text].
-
Kemp JM,
Powell TPS
(1971b)
The site of termination of afferent fibres in the caudate nucleus.
Philos Trans R Soc Lond B Biol Sci
262:413-427[Abstract/Free Full Text].
-
Lindefors N,
Ungerstedt U
(1990)
Bilateral regulation of glutamate tissue and extracellular levels in caudate-putamen by midbrain dopamine neurons.
Neurosci Lett
115:248-252[Web of Science][Medline].
-
Lisman JE,
Harris KM
(1993)
Quantal analysis and synaptic anatomy: integrating two views of hippocampal plasticity.
Trends Neurosci
16:141-147[Web of Science][Medline].
-
Maxwell DJ,
Christie WM,
Brown AG,
Ottersen OP,
Storm-Mathisen J
(1992)
Direct observations of synapses between L-glutamate-immunoreactive boutons and identified spinocervical tract neurones in the spinal cord of the cat.
J Comp Neurol
326:485-500[Web of Science][Medline].
-
McGeer DL,
McGeer EG,
Scherer U,
Singh K
(1977)
A glutaminergic corticostriatal pathway?
Brain Res
128:369-373[Web of Science][Medline].
-
Meshul CK,
Casey DE
(1989)
Regional, reversible ultrastructural changes in rat brain with chronic neuroleptic treatment.
Brain Res
489:338-346[Web of Science][Medline].
-
Meshul CK,
Tan S-E
(1994)
Haloperidol-induced morphological alterations are associated with changes in calcium/calmodulin kinase II activity and glutamate immunoreactivity.
Synapse
18:205-217[Web of Science][Medline].
-
Meshul CK,
Janowsky A,
Casey DE,
Stallbaumer RK,
Taylor B
(1992)
Effect of haloperidol and clozapine on the density of "perforated" synapses in caudate, nucleus accumbens, and medial prefrontal cortex.
Psychopharmacology (Berl)
106:45-52[Medline].
-
Meshul CK,
Stallbaumer RK,
Taylor B,
Janowsky A
(1994)
Haloperidol-induced morphological changes in striatum are associated with glutamate synapses.
Brain Res
648:181-195[Web of Science][Medline].
-
Ottersen OP
(1989)
Postembedding immunogold labelling of fixed glutamate: an electron microscopic analysis of the relationship between gold particle density and antigen concentration.
J Chem Neuroanat
2:57-66[Web of Science][Medline].
-
Ottersen OP,
Storm-Mathisen J
(1984)
Glutamate- and GABA-containing neurons in the mouse and rat brain, as demonstrated with a new immunocytochemical technique.
J Comp Neurol
229:374-392[Web of Science][Medline].
-
Paxinos G,
Watson C
(1982)
In: The rat brain in stereotaxic coordinates. London: Academic.
-
Penny GR,
Afsharpour S,
Kitai ST
(1986)
The glutamate decarboxylase-, leucine enkephalin-, methionine enkephalin- and substance P-immunoreactive neurons in the neostriatum of the rat and cat: evidence for partial population overlap.
Neuroscience
17:1011-1045[Web of Science][Medline].
-
Phend KD,
Weinberg RJ,
Rustioni A
(1992)
Techniques to optimize post-embedding single and double staining for amino acid neurotransmitters.
J Histochem Cytochem
40:1011-1020[Abstract].
-
Pierce JP,
Lewin GR
(1994)
An ultrastructural size principle.
Neuroscience
58:441-446[Web of Science][Medline].
-
Reynolds ES
(1963)
The use of lead citrate at high pH as an electron opaque stain in electron microscopy.
J Cell Biol
17:208-212[Free Full Text].
-
Seroogy KB,
Lundgren KH,
Tran TMD,
Guthrie KM,
Isackson PJ,
Gall CM
(1994)
Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs.
J Comp Neurol
342:321-334[Web of Science][Medline].
-
Small JV (1968) Measurement of section thickness. Paper
presented at Fourth European Regional Conference on Electron
Microscopy, Rome.
-
Smith Y,
Bennett BD,
Bolam JP,
Parent A,
Sadikot AF
(1994)
Synaptic relationships between dopaminergic afferents and cortical or thalamic input in the sensorimotor territory of the striatum in monkey.
J Comp Neurol
344:1-19[Web of Science][Medline].
-
Somogyi P,
Bolam JP,
Smith AD
(1981)
Monosynaptic cortical input and local axon collaterals of identified striatonigral neurons. A light and electron microscopic study using the Golgi-peroxidase transport-degeneration procedure.
J Comp Neurol
195:567-584[Web of Science][Medline].
-
Starr MS
(1995)
Antiparkinsonian actions of glutamate antagonists alone and with L-DOPA: a review of evidence and suggestions for possible mechanisms.
J Neural Transm Parkinson's Dis Dementia Sect
10:141-185[Web of Science][Medline].
-
Sterio DC
(1984)
Estimating numbers, mean sizes and variations in size of particles in 3-D specimens using disectors.
J Microsc
134:127-136[Medline].
-
Ungerstedt U,
Arbuthnott GW
(1970)
Quantitative recording of rotational behaviour in rats after 6-hydroxy-dopamine lesions of the nigrostriatal dopamine system.
Brain Res
24:485-493[Medline].
-
Voorn P,
Jorritsma-Byham B,
Van Dijk C,
Buijs RM
(1986)
Dopaminergic innervation of the ventral striatum in the rat: a light and electron-microscopical study with antibodies against dopamine.
J Comp Neurol
251:84-99[Web of Science][Medline].
-
Wilson CJ
(1987)
Morphology and synaptic connections of crossed corticostriatal neurons in the rat.
J Comp Neurol
263:567-580[Web of Science][Medline].
-
Wilson CJ,
Groves PM,
Kitai ST,
Linder JC
(1983)
Three-dimensional structure of dendritic spines in the rat neostriatum.
J Neurosci
3:383-398[Abstract].
-
Wright AK,
Hutton L,
Norrie L,
Arbuthnott GW
(1995)
Topographical patterns of efferents from the 'barrel' cortex in rat.
Brain Res Assoc Abstr
12:11.2.
-
Xu ZC,
Wilson CJ,
Emson PC
(1989)
Restoration of the corticostriatal projection in rat neostriatal grafts: electron-microscopic analysis.
Neuroscience
29:539-550[Web of Science][Medline].
-
Xu ZC,
Wilson CJ,
Emson PC
(1991)
Restoration of thalamostriatal projections in rat neostriatal grafts: an electron microscopic analysis.
J Comp Neurol
303:22-34[Web of Science][Medline].
-
Yung KKL,
Smith AD,
Levey AI,
Bolam JP
(1996)
Synaptic connections between spiny neurons of the direct and indirect pathways in the neostriatum of the rat: evidence from dopamine receptor and neuropeptide immunostaining.
Eur J Neurosci
8:861-869[Web of Science][Medline].
Copyright © 1998 Society for Neuroscience 0270-6474/98/18124732-12$05.00/0
This article has been cited by other articles:
|
|
|
|
 
B. H. Meurers, G. Dziewczapolski, T. Shi, A. Bittner, F. Kamme, and C. W. Shults
Dopamine Depletion Induces Distinct Compensatory Gene Expression Changes in DARPP-32 Signal Transduction Cascades of Striatonigral and Striatopallidal Neurons
J. Neurosci.,
May 27, 2009;
29(21):
6828 - 6839.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kirmse, A. Dvorzhak, S. Kirischuk, and R. Grantyn
GABA transporter 1 tunes GABAergic synaptic transmission at output neurons of the mouse neostriatum
J. Physiol.,
December 1, 2008;
586(23):
5665 - 5678.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Moss and J. P. Bolam
A Dopaminergic Axon Lattice in the Striatum and Its Relationship with Cortical and Thalamic Terminals
J. Neurosci.,
October 29, 2008;
28(44):
11221 - 11230.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Liang, M. R. DeLong, and S. M. Papa
Inversion of Dopamine Responses in Striatal Medium Spiny Neurons and Involuntary Movements
J. Neurosci.,
July 23, 2008;
28(30):
7537 - 7547.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Brown, A. J. Baucum, M. A. Bass, and R. J. Colbran
Association of Protein Phosphatase 1{gamma}1 with Spinophilin Suppresses Phosphatase Activity in a Parkinson Disease Model
J. Biol. Chem.,
May 23, 2008;
283(21):
14286 - 14294.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-H. Chen, B. K. Harvey, A. F. Hoffman, Y. Wang, Y.-H. Chiang, and C. R. Lupica
MPTP-induced deficits in striatal synaptic plasticity are prevented by glial cell line-derived neurotrophic factor expressed via an adeno-associated viral vector
FASEB J,
January 1, 2008;
22(1):
261 - 275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Nadjar, J. M. Brotchie, C. Guigoni, Q. Li, S.-B. Zhou, G.-J. Wang, P. Ravenscroft, F. Georges, A. R. Crossman, and E. Bezard
Phenotype of Striatofugal Medium Spiny Neurons in Parkinsonian and Dyskinetic Nonhuman Primates: A Call for a Reappraisal of the Functional Organization of the Basal Ganglia.
J. Neurosci.,
August 23, 2006;
26(34):
8653 - 8661.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. H. Gillingwater, C. A. Ingham, K. E. Parry, A. K. Wright, J. E. Haley, T. M. Wishart, G. W. Arbuthnott, and R. R. Ribchester
Delayed synaptic degeneration in the CNS of Wlds mice after cortical lesion
Brain,
June 1, 2006;
129(6):
1546 - 1556.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. E. Kippin, S. Kapur, and D. van der Kooy
Dopamine Specifically Inhibits Forebrain Neural Stem Cell Proliferation, Suggesting a Novel Effect of Antipsychotic Drugs
J. Neurosci.,
June 15, 2005;
25(24):
5815 - 5823.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Picconi, D. Centonze, S. Rossi, G. Bernardi, and P. Calabresi
Therapeutic doses of L-dopa reverse hypersensitivity of corticostriatal D2-dopamine receptors and glutamatergic overactivity in experimental parkinsonism
Brain,
July 1, 2004;
127(7):
1661 - 1669.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Picconi, F. Gardoni, D. Centonze, D. Mauceri, M. A. Cenci, G. Bernardi, P. Calabresi, and M. Di Luca
Abnormal Ca2+-Calmodulin-Dependent Protein Kinase II Function Mediates Synaptic and Motor Deficits in Experimental Parkinsonism
J. Neurosci.,
June 9, 2004;
24(23):
5283 - 5291.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Chuhma, H. Zhang, J. Masson, X. Zhuang, D. Sulzer, R. Hen, and S. Rayport
Dopamine Neurons Mediate a Fast Excitatory Signal via Their Glutamatergic Synapses
J. Neurosci.,
January 28, 2004;
24(4):
972 - 981.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. N. Guzman, A. Hernandez, E. Galarraga, D. Tapia, A. Laville, R. Vergara, J. Aceves, and J. Bargas
Dopaminergic Modulation of Axon Collaterals Interconnecting Spiny Neurons of the Rat Striatum
J. Neurosci.,
October 1, 2003;
23(26):
8931 - 8940.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Picconi, A. Pisani, D. Centonze, G. Battaglia, M. Storto, F. Nicoletti, G. Bernardi, and P. Calabresi
Striatal metabotropic glutamate receptor function following experimental parkinsonism and chronic levodopa treatment
Brain,
December 1, 2002;
125(12):
2635 - 2645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Zheng and C. J. Wilson
Corticostriatal Combinatorics: The Implications of Corticostriatal Axonal Arborizations
J Neurophysiol,
February 1, 2002;
87(2):
1007 - 1017.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wang and V. M. Pickel
Preferential Cytoplasmic Localization of {delta}-Opioid Receptors in Rat Striatal Patches: Comparison with Plasmalemmal {micro}-Opioid Receptors
J. Neurosci.,
May 1, 2001;
21(9):
3242 - 3250.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.N.D. Kerr and J. R. Wickens
Dopamine D-1/D-5 Receptor Activation Is Required for Long-Term Potentiation in the Rat Neostriatum In Vitro
J Neurophysiol,
January 1, 2001;
85(1):
117 - 124.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. A. Glantz and D. A. Lewis
Decreased Dendritic Spine Density on Prefrontal Cortical Pyramidal Neurons in Schizophrenia
Arch Gen Psychiatry,
January 1, 2000;
57(1):
65 - 73.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Zhang, J. P. Steiner, G. S. Hamilton, T. P. Hicks, and M. O. Poulter
Regeneration of Dopaminergic Function in 6-Hydroxydopamine-Lesioned Rats by Neuroimmunophilin Ligand Treatment
J. Neurosci.,
August 1, 2001;
21(15):
RC156 - RC156.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction
