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5 Pathological Consequences of Aberrant Interaction Between the Cerebellum and Basal Ganglia

5 Pathological Consequences of Aberrant Interaction Between the Cerebellum and Basal Ganglia

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C.H. Chen et al.

clinical imaging studies have shown the presence of focal cerebellar lesions in

patients with dystonia (Sadnicka et al. 2012; Turgut et al. 1995; Zadro et al. 2008).

Surgical studies have shown a direct role of the cerebellum in dystonia since interventions in the deep cerebellar nuclei (dentatectomy in particular) ameliorate dystonia (Heimburger 1967; Zervas et al. 1967). Thus, the role of the cerebellum in

dystonia has been well documented.

Clear evidence that dystonia arises from a network disorder involving the basal

ganglia and the cerebellum is supported mainly through animal models (Brown and

Lorden 1989; Fremont et al. 2014; Neychev et al. 2008; Pizoli et al. 2002). Here, we

discuss data obtained from animal models of Rapid Onset Dystonia Parkinsonism

(RDP) (Calderon et al. 2011; Fremont et al. 2015). The mechanisms underlying this

disease provide an example as to how abnormal cerebellar activity can influence the

basal ganglia via the disynaptic pathway through the thalamus.


Rapid Onset Dystonia Parkinsonism (DYT12)

Rapid onset dystonia parkinsonism (RDP) was identified as a distinctive syndrome

in 1992. Dr. William Dobyns named the disorder RDP because of its rapid onset and

evolution of symptoms, the combination of dystonic and parkinsonian symptoms,

and its minimal response to L-Dopa (Dobyns et al. 1993). Since then, genetic studies of the disease have shown that at least eleven mutations (de Carvalho Aguiar

et al. 2004; Heinzen et al. 2014) in the ATP1A3 gene, located on chromosome 19,

produce loss of function of the α3 isoform of the Na+/K+-ATPase pump (sodium

pump). This is a protein that participates in the control of ionic gradients across the

cell membrane and has been extensively studied (Skou 1957).

A pharmacological model for RDP was developed to acutely mimick the loss-offunction mutations by using low concentrations of ouabain, an exquisitely selective

inhibitor of the sodium pump (Allen et al. 1970). Unexpectedly, instead of observing dystonia when ouabain was perfused into the basal ganglia, this animal model

showed parkinsonian symptoms including rigidity, akinesia, and tremor (Calderon

et al. 2011). In contrast, infusion of ouabain into the cerebellum was necessary and

sufficient to induce dystonia (Calderon et al. 2011; Fremont et al. 2014). Likewise,

a more recent genetic model designed to knockdown the α3 sodium pump using

RNA interference (shRNA) reproduced these pharmacological findings, confirming

that disruption of only the α3 isoform is sufficient to induce dystonia (Fremont et al.


Both pharmacologic and genetic (shRNA) models have shown that dystonia is

associated with erratic firing of cerebellar neurons (Fremont et al. 2014, 2015). In

vivo recordings from Purkinje and deep cerebellar nuclei cells (DCN) have shown

that there is high-frequency bursting activity during dystonic episodes. As Purkinje

cell activity is highly sensitive to partially blocking sodium pumps (Fremont et al.

2014), it was suggested that the erratic firing of DCN is the result of Purkinje cell

activity driving these cells.

7 Interactions Between the Basal Ganglia and the Cerebellum and Role…


Given that the cerebellum has this robust functional input to the basal ganglia,

and accumulating evidence has associated basal ganglia dysfunction with dystonia,

a logical hypothesis was that aberrant cerebellar activity might cause dystonia by

imposing this aberrant activity on the basal ganglia. An initial approach (Calderon

et al. 2011) showed that lesioning the centrolateral thalamus prevented cerebellar

induction of dystonia, suggesting that cerebellar-induced dystonia is the consequence of a dynamic interaction between the cerebellum and basal ganglia.

Importantly, striatal neurons exhibited significantly aberrant, and oftentimes bursting activity, during episodes of cerebellar-induced dystonia (Chen et al. 2014). This

type of irregular activity has been observed in patients with dystonia (Starr et al.

2004). An elegant set of experiments has also showed that optogenetic silencing of

intralaminar thalamic neurons lessened dystonia within seconds after thalamic

silencing (Chen et al. 2014). Together, these data demonstrate that aberrant activity

from the cerebellum can adversely impact striatal activity to cause dystonia.


Aberrant Cerebellar Activity May Prompt Dystonia

in Other Pathologies

Here, we have discussed RDP at length, a condition where aberrant interaction

between the cerebellum and basal ganglia has been studied in detail. However, there

are many different types of monogenic dystonia (Lohmann and Klein 2013), in

which human carriers of genetic mutations associated with dystonia exhibit abnormalities in both the basal ganglia and the cerebellum, and communication between

these structures may participate in the pathophysiology of the disease. Examples are:

Myoclonus Dystonia (DYT11)

This is an inherited dystonia caused by mutations in the SGCE gene that expresses

the protein ε-sarcoglycan. fMRI studies of these patients show cerebellar hyperactivation suggesting that the cortico-ponto-cerebello-thalamo-cortical system is

affected (van der Salm et al. 2013).

Early Onset Primary Dystonia (DYT1)

This is another inherited dystonia caused by mutations in the TOR1A gene that

expresses the protein Torsin A. This protein is widely expressed in the basal ganglia

and the cerebellum, especially in spines and dendrites of Purkinje cells (Puglisi

et al. 2013). Several studies using positron emission tomography (PET) have shown

patterns of increased metabolic activity in the midbrain, cerebellum, and thalamus

during sustained dystonia and in carriers of the DYT1 mutation, but not in normal


C.H. Chen et al.

controls (Eidelberg et al. 1998; Ulug et al. 2011). In transgenic mice that express the

human mutant of Torsin A (hmT1), there is increased glucose utilization in cerebellum and substantia nigra, pars compacta, and reduced activity in caudal-caudate

putamen suggesting an abnormal cerebellar–basal ganglia interaction as an important component of the etiology of the disease (Zhao et al. 2011).

Whispering Dysphonia (DYT4)

This is a monogenic dystonia that is caused by mutations in the TUBB4A gene—a

gene that expresses dimeric proteins that constitute neuronal microtubules. It is suggested that these mutations may produce aberrant connections due to axon guidance

defects and dysfunction in synaptic and/or axonal transport of proteins. Structural

magnetic resonance images of the brain from these patients seem normal, suggesting a specifically functional disruption (Lohmann et al. 2013). Interestingly, hypomyelinization with atrophy of the basal ganglia and the cerebellum (H-ABC) is a

disease within the DYT4 familiy characterized by mutations in the same TUBB4A

gene, but often produces more extreme symptoms (Ferreira et al. 2014; Lohmann

et al. 2013). It is suggested that aberrant communication between the cerebellumbasal ganglia may play a significant role in these pathologies. Detailed functional

studies in patients with DYT4 and H-ABC are required to determine the role of

aberrant communication between cerebellum-basal ganglia in these patients.

Blepharospasm is a focal dystonia in which aberrant cerebello-basal ganglia

communication may play a critical role in its pathology. Apart from the multiple

disturbances of the basal ganglia associated with blepharospasm such as striatal

gliosis and putamen degeneration (Larumbe et al. 1993) functional studies in

patients with blepharospasm have recently shown that the cerebellum is an essential

contributor to the disease (Yang et al. 2014). Further functional studies are required

to better understand how functional defects in this network result in the pathology

and degeneration observed in the basal ganglia.

Syndromes Associated with Mutations in the α3 sodium pump

Motor control structures, such as the basal ganglia, cerebellum, thalamus and cortex

seem to be particularly sensitive to mutations in the α3 isoform of the sodium pump:

(1) the majority of pathological conditions associated with these mutations are associated with motor disorders in humans and animal models (Calderon et al. 2011; de

Carvalho Aguiar et al. 2004; Fremont et al. 2015). (2) The sodium pump is an

important regulator of brain excitability. It contributes to the after-hyperpolarization

of the cell (Gulledge et al. 2013). (3) Sodium pump controls intrinsic activity of

particular neuronal cell types, and dysfunctional sodium pumps may convert tonic

intrinsic firing to erratic firing (Fremont et al. 2014).

Mutations in the α3 sodium pump have been found in RDP (described before),

alternating hemiplegia of childhood (AHC) and cerebellar ataxia, areflexia, pes

7 Interactions Between the Basal Ganglia and the Cerebellum and Role…


cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome (Sweney

et al. 2015). Specific dysfunction of one or more of these motor control structures

may be sufficient to recapitulate the resulting symptomatology. However, given the

importance of communication between these structures, as exemplified by RDP,

altered communication between the cerebellum, basal ganglia and other areas cannot be discounted. Further mechanistic studies of these syndromes are necessary to

understand their pathophysiology.


Parkinson’s Disease

A hallmark of this disease is the loss of dopaminergic neurons of the substantia

nigra pars compacta, resulting in the manifestation of tremor, rigidity, bradykinesia,

and akinesia. However, more recent data suggests that cerebellar interactions with

the basal ganglia may contribute to the symptoms of Parkinson's disease (Martinu

and Monchi 2013; Wichmann et al. 2011; Wu and Hallett 2013). Several studies

indicate that cerebellar activity is also abnormal in Parkinson's disease (Ghaemi

et al. 2002; Rascol et al. 1997). In parkinsonian patients (Lenz et al. 1988) and in

nonhuman primate models of the disease (Guehl et al. 2003), oscillatory activity

similar to tremor frequencies has been recorded in thalamic areas that receive cerebellar, but not basal ganglia inputs. Furthermore, several studies have suggested

that targeting the cerebellar recipient zone in the thalamus is effective for treating

parkinsonian tremor (Narabayashi et al. 1987). Thus, it is plausible that abnormal

activity in cerebellar circuits may produce parkinsonian tremor. Additionally, deep

brain stimulation of the subthalamic nucleus reduces motor symptoms in Parkinson's

disease while normalizing cerebellar activity and function (Hilker et al. 2004).

Therefore, these findings suggest that altered interactions between the basal ganglia

and cerebellum may contribute to symptoms of Parkinson’s disease.


Psychiatric Disorders

Disorders like DYT11, DYT12 and Parkinson’s disease where the cerebellum-basal

ganglia network is altered often include significant psychiatric symptoms like anxiety, fear and depression along with their apparent motor dysfunctions (Brashear

et al. 2007, 2012; Peall et al. 2011). While a discrete pathway to generate these

psychiatric dysfunctions has yet to be described, it is possible that cerebellar interactions with the basal ganglia might play a role. Indeed, the role of cerebellar–basal

ganglia interactions in psychiatric dysfunctions seems to be an open and promising

area for future studies.


C.H. Chen et al.


The basal ganglia and the cerebellum are two major subcortical brain regions

involved in motor control but evidence for an interaction between these regions has

remained scant until recently. Multiple lines of evidence described in this chapter

provide strong support for functionally relevant interactions between the cerebellum and the basal ganglia network in normal and in pathological conditions. Future

studies should aim at determining the mechanisms and functional consequences of

these interactions. This could lead to the development of novel therapeutic tools to

treat pathologies in which aberrant interaction between these structures plays a

prominent role.


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Chapter 8

Signaling Mechanisms in L-DOPA-Induced


Cristina Alcacer, Veronica Francardo, and M. Angela Cenci



Parkinson’s disease (PD) is characterized by typical movement disorders, in particular, loss of spontaneous movements (akinesia) and slowness of movement

(bradykinesia). These motor symptoms are due to the degeneration of nigrostriatal

dopamine (DA) neurons and the ensuing loss of DA in the striatum. The DA precursor L-3,4 dihydroxyphenylalanine (L-DOPA) remains the most effective treatment

for PD. However, after an initial period of full efficacy, this treatment is complicated

by L-DOPA-induced dyskinesia (LID), abnormal involuntary movements (AIMs)

having both hyperkinetic and dystonic components. LID has been estimated to

affect approximately 80 % of PD patients within 10 years (Rascol 2000; Rascol

et al. 2015; Van Gerpen et al. 2006). A better understanding of the neuronal mechanisms underlying the development of LID is essential to identify effective therapeutic strategies (Cenci and Lindgren 2007; Jenner 2008).

Among all the basal ganglia nuclei, the striatum is attributed a pivotal role in

generating parkinsonian and dyskinetic motor features, as indicated by the marked

effects of striatum-targeted interventions (Bateup et al. 2010; Fasano et al. 2010;

Santini et al. 2007). At least 90 % of all striatal neurons are the GABAergic spiny

projection neurons (SPNs). There are however two distinct categories of SPNs,

those projecting to the substantia nigra reticulata and the internal globus pallidus,

so-called “direct pathway” spiny projection neurons (dSPNs) (Gong et al. 2003;

Kawaguchi et al. 1990) and those projecting to the external globus pallidus, the

C. Alcacer, Ph.D. (*) • V. Francardo, M.D. • M.A. Cenci, M.D., Ph.D.

Basal Ganglia Pathophysiology Unit, Department of Experimental Medical Sciences,

Lund University, BMC F11, Lund 221 84, Sweden

e-mail: cristina.alcacer@med.lu.se; veronica.francardo@med.lu.se;


© Springer International Publishing Switzerland 2016

J.-J. Soghomonian (ed.), The Basal Ganglia, Innovations in Cognitive

Neuroscience, DOI 10.1007/978-3-319-42743-0_8


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