In Context
Clinical preview
Parkinson’s disease and thalamus: facts and fancy
The hallmark feature of Parkinson’s
disease is the degeneration of
dopaminergic neurons in the ventro-
lateral region of the substantia nigra
pars compacta, accompanied by
dopamine striatal deficit and accu-
mulation of aggregated α-synuclein
(known as Lewy bodies) in the
remaining neurons, as well as in other
brainstem nuclei, amygdala, and
cortical regions. Dopamine deficiency
leads to a cascade of functional
changes in neuronal activity in basal
ganglia circuits, which are ultimately
responsible for the cardinal features of
Parkinson’s disease.
Modulation of striatal activity is
a fundamental component of basal
ganglia function. The excitability of
striatal medium spiny neurons (MSNs)
is modulated by the nigrostriatal
dopaminergic projection, intrastriatal
cholinergic and GABAergic inhibition,
and cortico and thalamic glutamatergic
input. Dopaminergic striatal depletion
in Parkinson’s disease disrupts the
corticostriatal balance leading to
increased activity in the striatopallidal
direct circuits, decreased activity in
indirect circuits, and abnormal basal
ganglia output activity. Whereas many
studies have defined in great detail the
origin of motor features associated
with dopamine striatal depletion and
changes in the motor circuit, much
less attention has been given to the
putative role of other projections, such
as the thalamus.
A new report by Parker and
colleagues, describes how dopamine
depletion causes a miscommunication
between the basal ganglia and the
thalamus. Using optogenetics and
voltage clamp-recordings from MSNs
in brain slices from transgenic mice,
these investigators noted that this
miscommunication led to decreased
synaptic strength at thalamic
inputs to the direct striatopallidal
projection in parkinsonian animals.
www.thelancet.com/neurology Vol 15 June 2016
In control animals, MSNs in the direct
pathway displayed larger excitatory
postsynaptic current amplitudes
than ones in the indirect pathway,
both in the thalamostriatal and
corticostriatal projections. After
dopamine depletion, no change was
shown in the corticostriatal pathway,
whereas the excitatory postsynaptic
current amplitudes in MSNs in the
indirect pathway were substantially
larger than those in the direct
thalamostriatal pathway, reversing
the normal excitatory postsynaptic
current amplitude ratio between
direct and indirect MSNs. No change
in presynaptic glutamate release
at corticostriatal or thalamostriatal
synapses was found in MSNs in the
direct pathway, suggesting that
the excitatory postsynaptic current
amplitude shift was not mediated by
presynaptic modifications. Also, there
was no difference in the density of
parafascicular nucleus cells between
control and parkinsonian animals, in
contrast with some previous studies.
Conversely, the AMPA/NMDA receptor
ratio was selectively decreased at
thalamostriatal direct MSNs but not
indirect MSNs, suggesting that this
reorganisation of thalamostriatal
excitatory input might be related to
changes in postsynaptic function.
These findings led authors to hypo-
thesise that thalamostriatal inputs
onto MSNs giving rise to the direct
circuit might be actively contributing
to reduce spontaneous motor activity
in parkinsonian mice. Accordingly, they
blocked the thalamostriatal projection
by chemogenetics and optogenetics
and reversed the imbalance between
the direct and indirect pathways,
successfully restoring normal
behaviour in parkinsonian animals.
Overall, this study implicates the mid-
thalamic nuclei in the pathophysiology
of Parkinson’s disease. This concept is
not new. These nuclei are well known to
send major glutamatergic projections
to the striatum, subthalamic nucleus,
globus pallidus, and substantia Neuron and The Lancet Neurology
nigra. However, the contribution of are both published by Elsevier
these nuceli to the pathophysiology
of Parkinson’s disease is unclear. In For more information about the
addition to the cell loss found in the features of Parkinson’s disease
centromedian–parafascicular complex see Seminar Lancet 2015;
386: 896–912
in patients with Parkinson’s disease
For more information about
and in animal studies, increased basal ganglia see Series Lancet
metabolic activity and neuronal firing 2014; 384: 523–31
have been described in parkinsonian For Parker and colleagues’
animal models, and kainate- paper see Neuron 2016;
89: 734–40
induced chemical ablation of the
For more information about
centromedian–parafascicular complex
parafascicular nucleus cells in
in MPTP monkeys did not convey human beings see Brain 2000;
any motor benefit, a set of findings 123: 1410–21
that are difficult to reconcile. The For more information about
physiological role of the intralaminar mid-thalamic nuclei see
J Comp Neurol 2005; 483: 143–53
nuclei–basal ganglia interaction is
For more information about cell
not well defined, but it is likely to loss in the centromedian–
be modulatory rather than directly parafascicular see
modifying input and output activity Brain Struct Funct 2014;
219: 381–94
in the manner established for the
For more information about the
nigrostriatal dopaminergic system or parkinsonian state see
the glutamatergic subthalamopallidal Front Neuroanat 2015; 9: 5
projections. In conclusion, this new For more information about
report revives interest in the role of the MPTP monkeys see Mov Disord
2008; 23: 708–15
thalamus in Parkinson’s disease using
state-of-the-art methods. However,
the overall information regarding the
functional state and cell changes in
the intralaminar nuclei in Parkinson’s
disease is far from clear and requires
further studies. It is noteworthy
that the centromedian–parafascicular
complex of the thalamus is not
considered as a useful surgical target for
any movement or behavioural disorder
in patients.
We declare no competing interests.
Javier Blesa, Inés Trigo-Damas,
*José A Obeso
jobeso.hmcinac@hmhospitales.com
HM Hospitales, Centre for Integrative Neuroscience
AC, Hospital Universitario HM Puerta del Sur,
Mostoles and CEU San Pablo University and Center
for Networked Biomedical Research on
Neurodegenerative Diseases, Institute Carlos III,
Madrid, Spain
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