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Brain 2009: 132; 285–287

| 285



Synaptic plasticity, dopamine and Parkinson’s
disease: one step ahead
The progressive loss of substantia nigra pars compacta neurons
that characterizes Parkinson’s disease pathology leads to impaired
levels of dopamine in several key structures of the basal ganglia
neuronal circuit and subsequent alteration of the thinly regulated
balance between activities of the output nuclei—the internal segment of the globus pallidus and the substantia nigra pars reticulata—that is considered essential for normal function of the circuit
(Fig. 1A).
Although many advances have been made in the field of
Parkinson’s disease research, the precise mechanisms leading to
symptom onset are still far from being unravelled. An impairment
of the ability of neurons in the basal ganglia circuit to undergo
synaptic plasticity is a key component of several current theories
explaining neuronal network abnormalities during this neurodegenerative disease (Calabresi et al., 2006). Synaptic plasticity, in
the form of long-term depression (LTD) and long-term potentiation (LTP), is one of the most fascinating properties of the brain
and is represented by the ability to encode and retain memories
via the activity-dependent functional and morphological remodelling of synapses (Di Filippo et al., 2008).
Interestingly, biochemical and electrophysiological studies carried out in experimental models have demonstrated that dopamine
plays a crucial role within the basal ganglia in regulating longlasting changes in synaptic strength (Calabresi et al., 2007).
Since the striatum represents the main input station of the basal
ganglia, the large majority of experimental electrophysiology studies on basal ganglia neuroplasticity have focused on this neural
structure. The crucial role played by dopamine in the modulation
of synaptic plasticity in the basal ganglia has been evident since
the first description of striatal LTD and LTP (Calabresi et al., 1992;
Calabresi et al., 2007). The role of dopamine was then confirmed
by further studies on genetic models lacking the D2 dopamine
receptors and DARPP32 (the dopamine and cAMP-regulated
phosphoprotein 32 kDa) (Calabresi et al., 2007). Studies on experimental models of Parkinson’s disease have confirmed the link
between substantia nigra pars compacta neurons degeneration
and loss of the main forms of neuroplasticity (Calabresi et al.,
2007). In particular, by utilizing both toxic and genetic models
of Parkinson’s disease, it was shown that impairment in LTD and
LTP induction paralleled dopamine depletion and onset of the

characteristic symptoms of the disease (Calabresi et al., 1992;
Goldberg et al., 2005). The discovery of dopamine deficiency in
Parkinson’s disease led to the introduction of replacement therapy
with the dopamine precursor L-3,4-dihydroxyphenylalanine
(L-DOPA). Interestingly, treatment with L-DOPA was demonstrated to be able to restore LTP expression in the 6-OHDA experimental model of Parkinson’s disease (Picconi et al., 2003)
indicating that treatment with a drug able to ameliorate disease
symptoms is associated with the recovery of a selective form of
synaptic plasticity.
Another form of synaptic plasticity, named ‘depotentiation’,
which results from the reversal of established LTP by a low-frequency stimulation protocol, was also found to be dependent on
dopaminergic signalling and, interestingly, to be lost selectively in
an experimental model of L-DOPA-induced dyskinesia (Picconi
et al., 2003), a very disabling hyperkinetic long-term side effect
of the therapy with L-DOPA. The hypothesis of a link between
LTP alterations and Parkinson’s disease has also been directly
investigated in patients suffering from the disease. The presence
of an aberrant motor cortex plasticity in Parkinson’s disease and
the ability of L-DOPA of restoring physiological plasticity in nondyskinetic but not in dyskinetic patients has been demonstrated by
utilizing transcranial magnetic and median nerve stimulation
(paired associative stimulation protocol) (Morgante et al., 2006).
Nevertheless, to date, direct electrophysiological proof of the
inter-relation between basal ganglia synaptic plasticity, dopamine
and Parkinson’s disease in human patients has been lacking.
In this issue, Prescott et al. (2009) provide this lacking evidence
by studying synaptic plasticity in the substantia nigra pars reticulata of 18 Parkinson’s disease patients undergoing therapeutic
implantation of deep brain stimulating electrodes in the subthalamic nucleus. In particular, the authors recorded evoked field
potentials from one electrode while stimulating with single
pulses from a second electrode; and they utilized, as an LTP-inducing protocol, a high-frequency stimulation given during both OFF
and ON dopaminergic medication states. By utilizing this experimental approach, the authors show that high-frequency stimulation did not induce a lasting change in field potential amplitude in
Parkinson’s disease patients recorded in the OFF state and that,
interestingly, patients with a higher Unified Parkinson’s Disease

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| Brain 2009: 132; 285–287

Scientific Commentary

Fig. 1 The basal ganglia circuit. Potential implications of the LTP of GABAergic signals onto substantia nigra pars reticulata neurons.
(a) During physiological conditions the thinly regulated activity of the direct and indirect pathways controls the activity of the output
nuclei. (b) During Parkinson’s disease, in the absence of a pharmacological treatment, dopamine deficiency causes overactivity of the
indirect pathway and reduced activity of the inhibitory GABAergic direct pathway, disinhibiting the output nuclei and thus causing
excessive inhibition of the motor thalamus. In this condition, high frequency stimulation does not induce a lasting change in GABAergic
field potential amplitude in the substantia nigra pars reticulata. (c) After the administration of L-DOPA, the same high-frequency
stimulation protocol induces potentiation of the GABAergic field potential amplitudes, reducing the excessive inhibitory activity that the
output nuclei exert on the motor thalamus. (d) Finally, after the chronic administration of L-DOPA, uncontrolled potentiation of the
GABA-mediated inhibition of the output nuclei might result in long-term suppression of their firing rate which in turn might lead to
pathological disinhibition of the thalamus and the subsequent onset of pathological hyperkinetic behaviours, such as L-DOPA-induced
dyskinesias. Note that, in the Figure, inhibitory GABAergic connections are represented in red, excitatory glutamatergic connections in
green and dopaminergic connections in black.

Rating Scale score underwent less change in field potential
amplitude following high-frequency stimulation. Conversely, the
authors report that the same high-frequency stimulation protocol,
given following administration of L-DOPA, potentiated the field
potential amplitudes (LTP), suggesting that a widely used antiparkinsonian drug is able to mediate the induction/restoration
of a form of neuroplasticity in the human substantia nigra pars
reticulata. This latter, interesting, result provides human data to
support the theory of the central role of dopamine in the modulation of synaptic plasticity within the basal ganglia and in particular during Parkinson’s disease. The evidence that neurons from
substantia nigra pars reticulata are able to express a form of
extracellularly recorded synaptic plasticity after the administration
of L-DOPA represents a novel and appealing result but, as with
any interesting discovery, raises more questions than answers. It is

obvious that the study of synaptic plasticity in humans by utilizing
electrodes for deep brain stimulation represents an invasive procedure and it is thus not applicable to patients not undergoing
a deep brain stimulation procedure for therapeutic purposes. For
this reason, due to the absence of control conditions, it is impossible to know if neurons of human substantia nigra pars reticulata
are actually able to undergo LTP in physiological conditions and
thus to know if L-DOPA is really able to restore an impaired form
of neuroplasticity during Parkinson’s disease or per se induces
potentiation of the field potential amplitudes.
The fact that the data have been obtained in one of the output
nuclei of the basal ganglia is of particular interest. In the substantia nigra pars reticulata, striatal GABAergic inputs, subthalamic
nucleus glutamatergic inputs and dopaminergic inputs from the
substantia nigra pars compacta converge and the output signal

Scientific Commentary
is thought directly to modulate activity of thalamic neurons that, in
turn, activate cortical motor programmes. A crucial question then
arises. Where and how does L-DOPA exert its action? The effect
observed in the substantia nigra pars reticulata might indeed represent the indirect downstream effect of modulating the nucleus
striatum or the subthalamic nucleus rather than representing a
direct effect of L-DOPA on the substantia nigra pars reticulata.
It is also worth considering that the mechanisms by which L-DOPA
might potentially modulate the described form of synaptic plasticity remain unclear. Indeed, L-DOPA exerts its effects after transformation to dopamine (by dopamine- and non-dopaminecontaining cells) and to noradrenaline (by noradrenaline-containing cells) (Mercuri and Bernardi, 2005). Thus, the described effects
might not only depend on the activation of D1- and D2-like
dopamine receptors but also result from stimulation, in the substantia nigra pars reticulata, of - and b-adrenoceptors or of
unconventional dopaminergic sites (Mercuri and Bernardi, 2005).
Another crucial point deals with the potential interpretation, in
terms of relevance for the circuit dynamics, of the observed field
potential potentiation that followed the administration of L-DOPA
in this study. As already mentioned, GABAergic and glutamatergic
signals converge in the substantia nigra pars reticulata. The
authors’ hypothesis is that the field potentials described are
GABAergic in nature. During Parkinson’s disease, activity of the
GABAergic neurons of the output nuclei is thought to be
enhanced and to cause excessive inhibition of the thalamic
neurons. This inhibition of thalamic activity might thus act as a
‘brake’ on activity of the supplementary motor cortex resulting in
onset of the parkinsonian syndrome (Bezard et al., 2001) (Fig. 1B).
If this is the case, potentiation of GABAergic signals onto substantia nigra pars reticulata, by lowering neurons firing rate, could (at
least in part) mediate the beneficial symptomatic effects of LDOPA (Fig. 1C). Another crucial question then arises: ‘is it possible
that neuroplasticity also mediates the long-term complications of
L-DOPA therapy and, in particular, dyskinesias?’ It is well accepted
that, in order to avoid neuronal network destabilization, the
mechanisms underlying synaptic plasticity need to be finely regulated and, in experimental models of the disease, one crucial form
of homeostatic synaptic plasticity, depotentiation, is selectively lost
during dyskinesias (Picconi et al., 2003). Thus, it remains possible
that L-DOPA, via the continuous and uncontrolled increase of the
strength of GABAergic synapses onto output nuclei neurons may
lead to progressive destabilization of postsynaptic firing rates, virtually reducing these to zero and thus leading to pathological
disinhibition of thalamic nuclei and the onset of abnormal involuntary movements (Fig. 1D).
Although these and other questions might be inspired by the
work of Prescott et al., the results of the study published in the

Brain 2009: 132; 285–287

| 287

current issue certainly open the way to a new experimental
approach in the field of Parkinson’s disease research, strengthening the view of Parkinson’s disease as a ‘synaptopathy’ that can be
rapidly counteracted by the manipulation of a neurotransmitter
system. The hope is that, in the future, the study of human synaptic plasticity might shed light on the complex mechanisms underlying symptoms of the disease and the disabling long-term side
effects of treatment with L-DOPA.
Paolo Calabresi1,2 Nicola Biagio Mercuri2,3 and
Massimiliano Di Filippo1,2
Clinica Neurologica, Universita` di Perugia, Perugia, Italy
IRCCS Fondazione S. Lucia, Rome, Italy
Clinica Neurologica, Universita` di Roma Tor Vergata, Rome, Italy
Advance Access publication January 22, 2009

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