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THE ROLE OF THE SUBTHALAMIC NUCLEUS IN THE PATHOPHYSIOLOGY OF
PARKINSON’S DISEASE
Fabio Blandini
Laboratory of Functional Neurochemistry, IRCCS
C. Mondino Institute of Neurology, Pavia, Italy
Reprint requests to: Dr Fabio Blandini, Laboratory of Functional Neurochemistry, C.Mondino Institute of Neurology, Via
Palestro, 3 - 27100 Pavia, Italy.
E-mail: [email protected]
Many environmental and occupational chemicals are
known to affect the central and/or peripheral nervous
system, causing changes that may result in neurological and psychiatric disorders. Because of the limited
accessibility of the mammalian nervous tissue, new
strategies are being developed to identify biochemical
parameters of neuronal cell function, which can be
measured in easily obtained tissues, such as blood
cells, as potential markers of the chemically-induced
alterations occurring in the nervous system. This review includes a comparative analysis of the effects of
mercurials on calcium signalling in the neuroadrenergic PC12 cells and rat splenic T lymphocytes in an attempt to characterize this second messenger system as
KEY WORDS: Basal ganglia, dopamine, glutamate,
movement disorders, neuroprotection, substantia nigra.
FUNCT NEUROL 2001;16 (SUPPL.): 99-106
INTRODUCTION
Parkinson’s disease (PD) is a progressive,
neurodegenerative disorder, in which the capacity to execute voluntary movements is gradually lost. The clinical picture of PD includes
tremor, rigidity and bradykinesia. The pathologic hallmark of the disease is the degeneration of melanine-containing, dopaminerg i c
neurons of the substantia nigra pars compacta,
which leads to severe dopaminergic denervation of the corpus striatum. The dopaminergic
deficit of the nigrostriatal system is accompanied by functional modifications of the other
basal ganglia nuclei, which constitute the neural substrate for the expression of PD motor
symptoms. In the context of this alteration of
the basal ganglia circuitry activity, the subthal-
amic nucleus – the only excitatory nucleus of
the circuit – plays a prominent role.
THE BASAL GANGLIA CIRCUITRY
Proper execution of voluntary movements
results from the correct processing of sensorimotor information by a complex neural network, which includes the cerebral cortex, the
motor thalamus and the basal ganglia nuclei.
The basal ganglia circuit, which is functionally
interposed between the cortex and the thalamus, plays the major role in this process. The
basal ganglia nuclei process the inputs flowing
from the cortex to produce an output signal that
returns – via the motor thalamus – to the cortex, to modulate movement execution (1).
FUNCTIONAL NEUROLOGY (16) SUPPL. 4 2001
99
F. Blandini
The basal ganglia circuit consists of four nuclei: corpus striatum (or striatum), globus pal lidus, substantia nigra and subthalamic nucleus
(Fig. 1). The basal ganglia nuclei are interconnected, and their functional organization has
been extensively investigated over the past
decade. According to a very popular model (2,3),
the striatum – the main input nucleus of the circuit – transmits the flow of information received
from the cortex to the basal ganglia o u t p u t
nuclei, substantia nigra pars reticulata and medial
globus pallidus, via a direct and an indirect pathway originating from different subsets of striatal
neurons. In the direct pathway, striatal GABAergic neurons containing dynorphin as a co-trans-
mitter and expressing D1 dopamine receptors,
project monosynaptically to the substantia nigra
pars reticulata and medial globus pallidus. In the
indirect pathway, a subset of GABAergic neurons containing enkephaline and expressing D2
receptors project to the lateral globus pallidus,
which sends GABAergic projections to the STN.
In turn, the STN sends its glutamatergic (excitatory) efferents to the output nuclei and to the lateral globus pallidus. From the output nuclei, inhibitory, GABAergic projections reach the ventral lateral and ventral anterior nuclei of the motor thalamus. Thalamic nuclei then send glutamatergic projections to the motor cortex, thus
closing the loop (Fig. 1).
Output Nuclei
Fig. 1 - Simplified representation of the functional organization of the basal ganglia nuclei. SNc: substantia nigra pars
compacta; SNr: substantia nigra pars reticulata; STN: subthalamic nucleus; LGP: lateral globus pallidus; MGP: medial
globus pallidus.
100
FUNCTIONAL NEUROLOGY (16) SUPPL. 4 2001
Subthalamic nucleus and Parkinson’s disease
From the model, it follows that the subthalamic nucleus occupies a strategic position in the
circuitry. As repeatedly demonstrated by experimental studies, the subthalamic nucleus can
modulate the neuronal activity of both basal
ganglia output nuclei (4-6). In addition, recent
studies have shown that the subthalamic nucleus
receives direct excitatory projections from the
primary motor cortex (7) and, more importantly,
that the nucleus receives dopaminergic projections from the substantia nigra pars compacta
(8-10). The description of this additional connectivity has further increased the importance of
the subthalamic nucleus in the functional architecture of the basal ganglia, suggesting a more
independent role for this nucleus with respect to
the other components of the circuitry.
Functional changes associated with Parkinson’s
disease: role of the subthalamic nucleus
As mentioned above, the degeneration of
nigrostrial neurons that underlies PD causes a
cascade of changes, leading to a functional rearrangement of the basal ganglia circuitry. The
ultimate consequence of this phenomenon is the
increased activity of the subthalamic nucleus
and/or the basal ganglia output nuclei, which receive subthalamic projections. Enhanced activity of the output nuclei results in increased inhibitory control over the motor thalamus and
subsequent reduction of the thalamic, glutam a t e rgic output to the motor cortex. These
changes are likely to constitute the neural substrate for parkinsonian motor symptoms (1).
Numerous experimental studies have shown
that the subthalamic nucleus is central to the PDrelated enhancement of the basal ganglia output.
In animals, it is possible to replicate the anatomical damage of PD using pharmacological agents.
The two most popular techniques involve the intracerebral injection of 6-hydroxydopamine (6OHDA), in rodents (11), and the systemic (intracarotid) administration of 1-methyl-4-phenyl1,2,3,6-tetrahydropiridine (MPTP) to monkeys
(12). Both toxins produce, via different mechanisms, selective lesions of the nigrostriatal pathway. Using these animal models of PD, various
groups have found increased levels of neuronal
firing rate (13,14), glucose metabolism (15), and
mitochondrial enzyme activity (16,17) in the subthalamic nucleus and in its projection nuclei. In
rodents, the metabolic and electrophysiological
changes that affect the output nuclei, as a consequence of the nigrostriatal lesion, are prevented
by lesioning the subthalamic nucleus (18,19).
Human studies also support the primary role
of subthalamic hyperactivity in PD pathophysiology. For example, it has been reported that the
occurrence of a subthalamic hematoma caused
the disappearance of parkinsonian symptoms in
a PD patient (20). Furthermore, Lange et al. (21)
have reported down-regulation of NMDA receptors in the medial globus pallidus of PD patients,
which has been interpreted as a consequence of
the increased activity of subthalamic projections
to the medial globus pallidus. All these findings
have led to the introduction of a new, electrophysiological technique in the therapy of PD,
known as “deep brain stimulation” (22). This
technique relieves PD motor symptoms by stimulating subthalamic neurons at high frequencies
through locally implanted electrodes. The procedure induces the functional blockade (depolarization) of the nucleus and, as shown recently,
consistent changes in residual dopaminergic
transmission at nigrostriatal level (23,24).
Hypotheses on PD-related subthalamic overactivity: the role of dopaminergic mechanisms
According to the classical model of basal
ganglia organization, subthalamic hyperactivity
results from reduction of the inhibitory control
exerted by the lateral globus pallidus, possibly
inhibited by overactive striato-pallidal, GABAergic, neurons (2). This is one of the controversial
points of the model. In fact, instead of showing a
reduction, recent studies have found increased
pallidal activity in both rodent (16,25) and pri-
FUNCTIONAL NEUROLOGY (16) SUPPL. 4 2001
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F. Blandini
mate models of PD (17). In addition, Hassani et
al. (26) have demonstrated that complete lesioning of the globus pallidus causes a slight increase
in the firing rate of subthalamic neurons, which
is far less pronounced than the increase observed
in animals with nigrostriatal damage. These data
suggest that an additional, if not alternative, explanation for the PD-related subthalamic hyperactivity should be considered.
As mentioned above, emerging evidence
shows that dopamine plays an important role at
subthalamic level. In addition to receiving
dopaminergic projections from the substantia nigra pars compacta (8-10), subthalamic neurons
have dopamine receptors that mediate their response to a variety of dopaminergic drugs (14,2731). Consequently, it is likely that subthalamic
dopaminergic mechanisms are directly involved
in the basal ganglia functional changes associated
with PD. Indeed, the density of subthalamic,
dopamine D2 receptors increases in rats bearing a
nigrostriatal lesion (28,32), while marked loss of
dopaminergic innervation has been reported in
MPTP-treated monkeys (33). As a consequence,
neuronal and motor responses to intra-subthalamic administration of dopaminergic agonists change
dramatically after a nigrostriatal lesion (14,30,34).
Moreover, Mukhida et al. have recently shown
that the use of intra-subthalamic, dopaminergic
transplants enhances the sensorimotor behavioral
recovery in hemiparkinsonian rats (35).
Taken together, these data indicate that
dopamine plays a central role in the regulation
of subthalamic activity and that degeneration
of the dopamine neurons of the substantia nigra
affects subthalamic activity directly, inducing a
dopaminergic “denervation” of the nucleus.
SUBTHALAMIC OVERACTIVTY AND NIGRAL DEGENERATION: IS THERE A LINK?
Although the substantia nigra pars compacta
is not considered a typical target of subthalamic
projections, there is solid evidence that subthala-
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mic neurons send glutamatergic fibers to nigral
dopaminergic neurons, too (36). Through this excitatory pathway, the subthalamic nucleus is able
to affect the activity of nigral neurons (37).
Therefore, the subthalamic hyperactivity occurring in PD also has repercussions on residual
neurons of the substantia nigra pars compacta.
In addition to being a neurotransmitter, glutamate can also be a toxin. Excessive stimulation of
the glutamate receptor, particularly the N-methylD-aspartate subtype, causes cell death, which can
be of the necrotic (38) or apoptotic (39) type, or
both (40). Glutamate toxicity has been evoked in
the pathogenesis of PD, although via an indirect
mechanism. In fact, although glutamate is likely
to play a direct role in acute neurological disorders, such as hypoxic/ischemic brain damage –
which is accompanied by massive release of glutamate (41) – this is unlikely to happen in a chronic, slowly evolving disorder, such as PD. However, glutamate can become neurotoxic – even at
physiological concentrations – in the presence of
a state of cellular energetic impairment, through a
mechanism known as indirect excitotoxicity
(42,43). This mechanism may very well occur in
the nigral neurons of PD patients, which are exceedingly vulnerable to toxic insults due to a
number of specific conditions, the most important
being mitochondrial enzyme complex I deficiency (44). The increase in glutamatergic inputs to
the subtantia nigra pars compacta, originating
from the subthalamic nucleus, may therefore interact with the bioenergetic defects, thus triggering or – more likely – aggravating the progression
of the degenerative process (45). A vicious circle
may ensue, with the nigrostriatal damage causing
subthalamic hyperactivity that, in turn, could sustain nigrostriatal degeneration. Indeed, in rats, a
subthalamic nucleus lesion protects neurons of the
substantia nigra pars compacta against the toxicity
of 6-OHDA (46) and prevents transneuronal degeneration of the substantia nigra pars reticulata
(47). More recently, Nakao et al. (48) have shown
that previous ablation of the subthalamic nucleus
attenuates the loss of nigral dopaminergic neurons
Subthalamic nucleus and Parkinson’s disease
by intrastriatal administration of neurotoxin 3-nitropropionic acid.
Thus, in addition to the role it plays in the
development of PD motor symptoms, the subthalamic nucleus may also be directly involved
in the mechanisms underlying the progression of
the neurodegenerative process.
PHARMACOLOGICAL BLOCKADE OF SUBTHALAMIC OVERACTIVITY: A NEUROPROTECTIVE TOOL?
From what has been discussed so far, it follows that, in addition to the symptomatic effects
(amelioration of PD motor symptoms), the
blocking of PD-related subthalamic hyperactivity might also have a neuroprotective effect. Reduction of enhanced glutamatergic transmission
has been recently suggested as an alternative approach to the treatment of PD (49,50). Indeed,
the use of glutamate antagonists – as both symp-
tomatic and neuroprotective agents – has proved
beneficial in numerous experimental studies
(49,50). However, the general limitation of the
use of these drugs is that glutamate receptors are
widespread in the brain. Thus, if a glutamate antagonist is given systemically, it will affect glutamatergic transmission outside the basal ganglia circuitry as well (even if the drug targets a
specific glutamate receptor subtype), which is
not desirable. For these reasons, we have recently studied the effects of selective blockade of
glutamatergic transmission, at subthalamic level,
on the development of a nigrostriatal lesion and
the associated functional changes in the basal
ganglia nuclei (25). Using permanent cannulas
connected to subcutaneous pumps, we infused –
directly into the subthalamic nucleus – two glutamate antagonists acting on different receptor
subtypes, MK-801 (NMDA antagonist) and
NBQX (AMPA antagonist), in rats with an
evolving nigrostriatal lesion induced by 6OHDA (Fig. 2). Subthalamic infusion of MK-
Fig. 2 - Drawing illustrating the experimental design followed in the study (ref. 25). Six-hydroxydopamine (2.5 µg/µl)
was injected into the striatum, so as to induce a progressive, retrograde lesion in the substantia nigra pars compacta
(SNc), which is connected to the striatum by the medial forebrain bundle (mfb). At the same time, a permanent cannula
connected to a sub-cutaneous, osmotic mini-pump, was lowered into the subthalamic nucleus (STN). Pumps were loaded
with MK-801 (NMDA antagonist), or NBQX (AMPA antagonist), or saline and delivered the solutions – continuously –
for four weeks. After three weeks, animals were tested with systemic amphetamine (3 mg/kg, i.p.) for the presence of rotational behavior. At the fourth week, animals were sacrificed and brains were analyzed to determine cytochrome oxidase activity (functional evaluation) and Nissl staining (anatomical evaluation).
FUNCTIONAL NEUROLOGY (16) SUPPL. 4 2001
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F. Blandini
801, but not of NBQX, prevented the increase in
metabolic activity of basal ganglia output nuclei
and reduced the amphetamine-induced rotational behavior associated with nigrostriatal lesions.
In addition, animals treated with MK-801
showed a marked reduction of the nigral cell
loss caused by the toxin.
16.
17.
CONCLUDING REMARKS
The subthalamic nucleus plays a central role
in the functional changes affecting the basal ganglia circuitry in PD. The pathological hyperactivity of subthalamic neurons, which develops as a
consequence of the nigrostriatal degeneration,
constitutes the neural substrate for PD motor
symptoms. Subthalamic hyperactivity is also
likely to contribute to the progression of the degenerative process. Therefore, manipulation of
the subthalamic activity – possibly through selective pharmacological agents – may constitute
a valuable tool to achieve both symptomatic improvement and neuroprotection in PD patients.
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