Human Movement Disorders Research Articles

Deregulation of glutamate dehydrogenase in human neurologic disorders

Mammalian glutamate dehydrogenase is an allosterically regulated enzyme that is central to glutamate metabolism. It contributes to important cellular processes, including Krebs cycle anaplerotic mechanisms, energy production, and ammonia homeostasis. In addition to this housekeeping hGDH1, humans have acquired through duplication an hGDH2 isoenzyme expressed in neural tissues with distinct regulatory properties. There is increasing evidence that deregulation of human GDHs leads to human disorders. Thus, in hGDH1, regulatory mutations that attenuate GTP inhibition can result in the hyperinsulinism/hyperammonemia syndrome, which is often associated with epileptic seizures, mental retardation, and generalized dystonia. Also, transgenic overexpression of GLUD1 in neurons has resulted in age-dependent degeneration of the CA1 behippocampal region, associated with upregulation of α-synuclein and other proteins linked to major human movement disorders. With regard to hGDH2, a rare T1492G variation in the GLUD2 gene, resulting in substitution of Ala for Ser445 in the regulatory domain of hGDH2, interacts significantly with Parkinson's disease (PD) onset. In two independent Greek and one North American PD cohorts, Ser445Ala hemizygous males, but not heterozygous females, developed PD 6-13 years earlier than subjects with other genotypes. The Ala445-hGDH2 variant displays increased catalytic activity that is amenable to inhibition by estrogens. Enhanced glutamate oxidation by Ala445-hGDH2 is thought to accelerate nigral cell degeneration in hemizygous males, and inhibition of the overactive variant by estrogens may protect heterozygous females. Hence, deregulation of hGDH1 and hGDH2 may play a role in degenerative processes, so these observations identify novel targets for therapeutic intervention in human disorders.

Essential tremor, the cerebellum, and motor timing: towards integrating them into one complex entity.

Essential tremor (ET) is the most common movement disorder in humans. It is characterized by a postural and kinetic tremor most commonly affecting the forearms and hands. Isolated head tremor has been found in 1-10% of patients, suggesting that ET may be a composite of several phenotypes. The exact pathophysiology of ET is still unknown. ET has been repeatedly shown as a disorder of mild cerebellar degeneration, particularly in postmortem studies. Clinical observations, electrophysiological, volumetric and functional imaging studies all reinforce the fact that the cerebellum is involved in the generation of ET. However, crucial debate exists as to whether ET is a neurodegenerative disease. Data suggesting that it is neurodegenerative include postmortem findings of pathological abnormalities in the brainstem and cerebellum, white matter changes on diffusion tensor imaging, and clinical studies demonstrating an association with cognitive and gait changes. There is also conflicting evidence against ET as a neurodegenerative disease: the improvement of gait abnormalities with ethanol administration, lack of gray matter volume loss on voxel-based morphometry, failure to confirm the prominent presence of Lewy bodies in the locus ceruleus, and other pathological findings. To clarify this issue, future research is needed to describe the mechanism of cellular changes in the ET brain and to understand the order in which they occur. The cerebellum has been shown to be involved in the timing of movement and sensation, acting as an internal timing system that provides the temporal representation of salient events spanning hundreds of milliseconds. It has been reported that cerebellar timing function is altered in patients with ET, showing an increased variability of rhythmic hand movements as well as diminished performance during predictive motor timing task. Based on current knowledge and observations, we argue that ET is essentially linked with cerebellar degeneration, or at least cerebellar dysfunction, together with disturbance of motor timing. We explain the context of our current understanding on this topic, highlighting possible clinical consequences for patients suffering from ET and future research directions.

Essential Tremor, the Cerebellum, and Motor Timing: Towards Integrating Them into One Complex Entity

Essential tremor (ET) is the most common movement disorder in humans. It is characterized by a postural and kinetic tremor most commonly affecting the forearms and hands. Isolated head tremor has been found in 1–10% of patients, suggesting that ET may be a composite of several phenotypes. The exact pathophysiology of ET is still unknown. ET has been repeatedly shown as a disorder of mild cerebellar degeneration, particularly in postmortem studies. Clinical observations, electrophysiological, volumetric and functional imaging studies all reinforce the fact that the cerebellum is involved in the generation of ET. However, crucial debate exists as to whether ET is a neurodegenerative disease. Data suggesting that it is neurodegenerative include postmortem findings of pathological abnormalities in the brainstem and cerebellum, white matter changes on diffusion tensor imaging, and clinical studies demonstrating an association with cognitive and gait changes. There is also conflicting evidence against ET as a neurodegenerative disease: the improvement of gait abnormalities with ethanol administration, lack of gray matter volume loss on voxel-based morphometry, failure to confirm the prominent presence of Lewy bodies in the locus ceruleus, and other pathological findings. To clarify this issue, future research is needed to describe the mechanism of cellular changes in the ET brain and to understand the order in which they occur. The cerebellum has been shown to be involved in the timing of movement and sensation, acting as an internal timing system that provides the temporal representation of salient events spanning hundreds of milliseconds. It has been reported that cerebellar timing function is altered in patients with ET, showing an increased variability of rhythmic hand movements as well as diminished performance during predictive motor timing task. Based on current knowledge and observations, we argue that ET is essentially linked with cerebellar degeneration, or at least cerebellar dysfunction, together with disturbance of motor timing. We explain the context of our current understanding on this topic, highlighting possible clinical consequences for patients suffering from ET and future research directions.

Axon guidance in the developing ocular motor system and Duane retraction syndrome depends on Semaphorin signaling via alpha2-chimaerin

Eye movements depend on correct patterns of connectivity between cranial motor axons and the extraocular muscles. Despite the clinical importance of the ocular motor system, little is known of the molecular mechanisms underlying its development. We have recently shown that mutations in the Chimaerin-1 gene encoding the signaling protein α2-chimaerin (α2-chn) perturb axon guidance in the ocular motor system and lead to the human eye movement disorder, Duane retraction syndrome (DRS). The axon guidance cues that lie upstream of α2-chn are unknown; here we identify candidates to be the Semaphorins (Sema) 3A and 3C, acting via the PlexinA receptors. Sema3A/C are expressed in and around the developing extraocular muscles and cause growth cone collapse of oculomotor neurons in vitro. Furthermore, RNAi knockdown of α2-chn or PlexinAs in oculomotor neurons abrogates Sema3A/C-dependent growth cone collapse. In vivo knockdown of endogenous PlexinAs or α2-chn function results in stereotypical oculomotor axon guidance defects, which are reminiscent of DRS, whereas expression of α2-chn gain-of-function constructs can rescue PlexinA loss of function. These data suggest that α2-chn mediates Sema3-PlexinA repellent signaling. We further show that α2-chn is required for oculomotor neurons to respond to CXCL12 and hepatocyte growth factor (HGF), which are growth promoting and chemoattractant during oculomotor axon guidance. α2-chn is therefore a potential integrator of different types of guidance information to orchestrate ocular motor pathfinding. DRS phenotypes can result from incorrect regulation of this signaling pathway.

A predictable worm: application of Caenorhabditis elegans for mechanistic investigation of movement disorders.

Ongoing investigations into causes and cures for human movement disorders are important toward the elucidation of diseases such as Parkinson's disease (PD) and dystonia. The use of animal model systems can provide links to susceptibility factors, as well as therapeutic interventions. In this regard, the nematode roundworm, Caenorhabditis elegans, is ideal for examining age-dependent neurodegenerative disease studies. It is genetically tractable, has a short lifespan, and a well-defined nervous system. Green fluorescent protein is readily visualized in C. elegans because it is a transparent organism, thus the nervous system and factors that alter the viability of neurons can be directly examined in vivo. Through expression of the human PD-associated protein (α-synuclein in the worm dopamine neurons), neurodegeneration is observed in an age-dependent manner. Furthermore, expression of the early-onset dystonia-related protein torsinA increases vulnerability to endoplasmic reticulum (ER) stress in C. elegans, because torsinA is located in the ER. Here we provide an overview of collaborative studies we have conducted that collectively demonstrate the usefulness of the nematode model to discern functional effectors of dopaminergic neurodegeneration and ER stress that translate to mammalian data in the fields of PD and dystonia. Taken together, the application of C. elegans toward the evaluation of genetic modifiers for movement disorders research has predictive value and serves to accelerate the path forward for therapeutic interventions.

Dtorsin, the Drosophila Ortholog of the Early-Onset Dystonia TOR1A (DYT1), Plays a Novel Role in Dopamine Metabolism

Dystonia represents the third most common movement disorder in humans. At least 15 genetic loci (DYT1-15) have been identified and some of these genes have been cloned. TOR1A (formally DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. However, the function of torsinA has yet to be fully understood. Here, we have generated and characterized a complete loss-of-function mutant for dtorsin, the only Drosophila ortholog of TOR1A. Null mutation of the X-linked dtorsin was semi-lethal with most male flies dying by the pre-pupal stage and the few surviving adults being sterile and slow moving, with reduced cuticle pigmentation and thin, short bristles. Third instar male larvae exhibited locomotion defects that were rescued by feeding dopamine. Moreover, biochemical analysis revealed that the brains of third instar larvae and adults heterozygous for the loss-of-function dtorsin mutation had significantly reduced dopamine levels. The dtorsin mutant showed a very strong genetic interaction with Pu (Punch: GTP cyclohydrolase), the ortholog of the human gene underlying DYT14 dystonia. Biochemical analyses revealed a severe reduction of GTP cyclohydrolase protein and activity, suggesting that dtorsin plays a novel role in dopamine metabolism as a positive-regulator of GTP cyclohydrolase protein. This dtorsin mutant line will be valuable for understanding this relationship and potentially other novel torsin functions that could play a role in human dystonia.

Expression and differential distribution of the shaker-related voltage-gated potassium channel family (KV1.x) in human hippocampus and neocortex

Background All excitable cells express voltage-gated potassium (KV) channels; in neurons they play an essential role in setting the resting membrane potential, controlling the firing frequency and duration of action potentials, and modulate neurotransmitter release. Due to this critical function as regulators of neuronal excitability, mutations and/or deletions in potassium channel subunit genes are associated with diverse clinical phenotypes (channelopathies), including seizure or movement disorders in both humans and animals. Additionally, voltage-gated potassium channels might play a crucial role in neurodegenerative and psychiatric disorders. For this reason, a better understanding of the occurrence and specific distribution of voltagegated potassium channels would be highly necessary. Several members of the KV1 subfamily have been found, but only KV1.1, KV1.2, KV1.4 and KV1.6 are widely expressed in the CNS in both human and rodent brain. However, unlike to rodents, little is known regarding the regional localization of these four members of the KV1 subfamily in human brain. Therefore we investigated, for the first time, the distribution of these four KV1 channel subtypes in human neocortex and hippocampus, which are known for their vulnerability to epilepsy and their importance for learning, memory and cognitive processes.

Probing conformational states of glutaryl-CoA dehydrogenase by fragment screening.

Glutaric acidemia type 1 is an inherited metabolic disorder which can cause macrocephaly, muscular rigidity, spastic paralysis and other progressive movement disorders in humans. The defects in glutaryl-CoA dehydrogenase (GCDH) associated with this disease are thought to increase holoenzyme instability and reduce cofactor binding. Here, the first structural analysis of a GCDH enzyme inthe absence of the cofactor flavin adenine dinucleotide (FAD) is reported. Theapo structure of GCDH from Burkholderia pseudomallei reveals a loss of secondary structure and increased disorder in the FAD-binding pocket relative to the ternary complex of the highly homologous human GCDH. After conducting a fragment-based screen, four small molecules were identified which bind to GCDH from B. pseudomallei. Complex structures were determined for these fragments, which cause backbone and side-chain perturbations to key active-site residues. Structural insights from this investigation highlight differences from apo GCDH and the utility of small-molecular fragments as chemical probes for capturing alternative conformational states of preformed protein crystals.

The early-onset torsion dystonia-associated protein, torsinA, is a homeostatic regulator of endoplasmic reticulum stress response

Early-onset torsion dystonia is the most severe heritable form of dystonia, a human movement disorder that typically starts during a developmental window in early adolescence. Deletion in the DYT1 gene, encoding the torsinA protein, is responsible for this dominantly inherited disorder, which is non-degenerative and exhibits reduced penetrance among carriers. Here, we explore the hypothesis that deficits in torsinA function result in an increased vulnerability to stress associated with protein folding and processing in the endoplasmic reticulum (ER), where torsinA is located. Using an in vivo quantitative readout for the ER stress response, we evaluated the consequences of torsinA mutations in transgenic nematodes expressing variants of human torsinA. This analysis revealed that, normally, torsinA serves a protective function to maintain a homeostatic threshold against ER stress. Furthermore, we show that the buffering capacity of torsinA is greatly diminished by the DYT1-associated deletion or mutations that prevent its translocation to the ER, block ATPase activity, or increase the levels of torsinA in the nuclear envelope versus ER. Combinations of transgenic Caenorhabditis elegans designed to mimic clinically relevant genetic modifiers of disease susceptibility also exhibit a direct functional correlation to changes in the ER stress response. Furthermore, using mouse embryonic fibroblasts (MEFs) from torsinA knockout mice, we demonstrated that loss of endogenous torsinA results in enhanced sensitivity to ER stress. This study extends our understanding of molecular mechanisms underlying dystonia, and establishes a new functional paradigm to evaluate therapeutic strategies to compensate for reduced torsinA activity in the ER as a means to restore homeostatic balance and neuronal function.

Rhythmic head movements in a horse reminiscent to human head-banging rhythmic movement disorder

Rhythmic head movements in a horse reminiscent to human head-banging rhythmic movement disorder

Top-Down Control of Saccades as Part of a Generalized Model of Proactive Inhibitory Control

Lo and colleagues have recently described a recurrent network model of inhibitory control of saccadic eye movements based on neurophysiological observations in the frontal eye field (FEF) and superior colliculus (SC) of rhesus monkeys. This model emphasizes the proactive, inhibition-based, tonic neuronal activity that prevents the eye from moving in a countermanding paradigm. In this review I discuss the model with respect to existing literature that the authors did not mention, suggesting that proactive inhibitory control extends far beyond saccadic control and provides an interesting framework to interpret several attentional and movement disorders in humans.

Role of Myosin Va in the Plasticity of the Vertebrate Neuromuscular Junction In Vivo

BackgroundMyosin Va is a motor protein involved in vesicular transport and its absence leads to movement disorders in humans (Griscelli and Elejalde syndromes) and rodents (e.g. dilute lethal phenotype in mice). We examined the role of myosin Va in the postsynaptic plasticity of the vertebrate neuromuscular junction (NMJ).Methodology/Principal Findings Dilute lethal mice showed a good correlation between the propensity for seizures, and fragmentation and size reduction of NMJs. In an aneural C2C12 myoblast cell culture, expression of a dominant-negative fragment of myosin Va led to the accumulation of punctate structures containing the NMJ marker protein, rapsyn-GFP, in perinuclear clusters. In mouse hindlimb muscle, endogenous myosin Va co-precipitated with surface-exposed or internalised acetylcholine receptors and was markedly enriched in close proximity to the NMJ upon immunofluorescence. In vivo microscopy of exogenous full length myosin Va as well as a cargo-binding fragment of myosin Va showed localisation to the NMJ in wildtype mouse muscles. Furthermore, local interference with myosin Va function in live wildtype mouse muscles led to fragmentation and size reduction of NMJs, exclusion of rapsyn-GFP from NMJs, reduced persistence of acetylcholine receptors in NMJs and an increased amount of punctate structures bearing internalised NMJ proteins.Conclusions/SignificanceIn summary, our data show a crucial role of myosin Va for the plasticity of live vertebrate neuromuscular junctions and suggest its involvement in the recycling of internalised acetylcholine receptors back to the postsynaptic membrane.

Pink1 suppresses α-synuclein-induced phenotypes in a Drosophila model of Parkinson’s disease

Parkinson's disease (PD) is the most prevalent human neurodegenerative movement disorder and is characterized by a selective and progressive loss of the dopaminergic neurons. Mutations in the genes parkin and PTEN-induced putative kinase 1 (PINK1) result in autosomal recessive forms of PD. It has been suggested that parkin and Pink1 function in the same pathway in Drosophila, with Pink1 acting upstream of parkin. Previous work in our laboratory has shown the ability of parkin to rescue an alpha-synuclein-induced PD-like phenotype in Drosophila. To investigate the ability of Pink1 to protect against alpha-synuclein-induced toxicity, we have performed longevity, mobility, and histological studies to determine whether Drosophila Pink1 can rescue the alpha-synuclein phenotypes. We have found that overexpression of Pink1 results in the rescue of the alpha-synuclein-induced phenotype of premature loss of climbing ability, suppression of degeneration of the ommatidial array, and the suppression of alpha-synuclein-induced developmental defects in the Drosophila eye. These results mark the first demonstration of Pink1 counteracting PD phenotypes in a protein toxicity animal model, and they show that Pink1 is able to impart protection against potentially harmful proteins such as alpha-synuclein that would otherwise result in cellular stress.

Traversing a wormhole to combat Parkinson’s disease

Human movement disorders represent a significant and unresolved societal burden. Among these, the most prevalent is Parkinson's disease (PD), a disorder afflicting millions worldwide. Despite major advances, stemming primarily from human genetics, there remains a significant gap in our understanding of what factors underlie disease susceptibility, onset, and progression. Innovative strategies to discern specific intracellular targets for subsequent drug development are needed to more rapidly translate basic findings to the clinic. Here we briefly review the recent contributions of research using the nematode roundworm Caenorhabditis elegans as a model system for identifying and characterizing gene products associated with PD. As a microscopic but multicellular and genetically tractable animal with a well-defined nervous system and an experimentally tenable lifespan, C. elegans affords significant advantages to researchers attempting to determine causative and therapeutic factors that influence neuronal dysfunction and age-associated neurodegeneration. The rapidity with which traditional genetic, large-scale genomic, and pharmacological screening can be applied to C. elegans epitomizes the utility of this animal for disease research. Moreover, with mature bioinformatic and functional genomic data readily available, the nematode is well positioned to play an increasingly important role in PD-associated discoveries.

Studies on the Spastic Rat: An Adequate Model for Human Spastic Movement Disorder?

to the editor: For the successful translation of basic research to humans, the adequacy of the animal model being studied is of crucial importance. With respect to the frequently occurring spastic syndrome, as a consequence of brain or spinal cord damage, the spastic rat tail is commonly applied as

Out FOXing Parkinson Disease: Where Development Meets Neurodegeneration

Parkinson disease (PD) is the most common neurodegenerative movement disorder in humans, but its cause in the majority of patients is unknown. Fewer than 10% of cases appear to be inherited, and only rarely are the known Mendelian mutations identified in patients with PD. In addition to genetic factors, environmental toxins—especially those affecting mitochondrial function—have also been implicated [1,2], demonstrating a clear role for gene–environment interactions in most cases of sporadic PD. Patients afflicted with PD experience slow, selective, often asymmetric loss of dopaminergic (DA) neurons projecting from the substantia nigra (SN) to the striatum, but not of DA neurons located elsewhere in the brain (e.g., ventral tegmental area and retina). Once more than 80%–90% of DA neurons in the SN are lost, patients suffer the characteristic symptoms of tremor, slow movements (bradykinesia), rigidity, and postural instability. To study PD, researchers have used two basic types of animal models: (1) acute lesioning of DA neurons/tracts, either by surgery or toxic insult, and (2) genetic models that rely on expression of one of the rare, dominant, and highly penetrant mutations that cause PD or knockout of a similar, recessively inherited allele (e.g., α-synuclein, Parkin, and leucine-rich repeat kinase-2 [LRRK2]). Although these models have led to huge advances in our understanding of PD—implicating mitochondrial dysfunction, oxidative damage, and protein handling systems in pathogenesis—they typically either fail to recapitulate the gradual nature of this degenerative disease or lack the defining pathology (e.g., Parkin and α-synuclein transgenic mice fail to show progressive nigrostriatal degeneration, although rotenone-treated mice do show Lewy bodies (intracytoplasmic inclusions that are composed primarily of α-synuclein and ubiqutin)) [3,4]. Because no single animal model is likely to be sufficient for the study of any particular human neurodegenerative disease, new models are needed to accelerate our ability to devise and test improved disease-altering therapies. It is in this regard that a new paper in PLoS Biology by Kittappa et al. [5] warrants special attention. They demonstrate that knockout of a transcription factor FoxA2, which is critical for DA neuron specification and survival in mice causes a late-onset, asymmetric degenerative condition affecting motor systems in a manner very similar to PD. This model is entirely distinct in its basic mechanism from the aforementioned models, because it involves partial loss of a transcription factor that is critical for DA neuron cell fate. One of the most striking features of the majority of adult-onset neurodegenerative diseases is their regional or cell-type specificity in humans. Yet, many of the known causative mutations reside in proteins that are widely expressed throughout the central nervous system, such as synuclein, LRK2, and Parkin in PD, beta amyloid and presenilin-1 (PS1) in Alzheimer disease, and tau and progranulin in frontotemporal dementia. The current study in mice, and previous work in humans and other model organisms, highlight the potential role that neurodevelopmental factors may play in the cell-type–specific or regional neuronal vulnerability seen in neurodegenerative disease [6,7] As this work by Kittappa and colleagues demonstrates, understanding early developmental processes such as cell-type specification and survival may have major implications for aging-related diseases.

Evaluation of a wearable orthosis and an associated algorithm for tremor suppression

We describe a wearable orthosis and an associated algorithm for the simultaneous assessment and treatment of essential tremor, one of the most common movement disorders in humans involving an overactivity of the olivo-cerebellar pathways. A motor providing effective viscosity is fixed on a wearable orthosis in the upper limbs. The motor is controlled by a personal computer with software processing in real time the position and rate of rotation of the joint detected by a chip gyroscope. The orthosis can be used in a monitoring mode and in an active mode. The range of tremor suppression of the signals above the orthosis operational limit ranges from about 3% (percentile 5) to about 79% (percentile 95) in relation to energy in the monitoring mode. Considering both postural and kinetic, the mean tremor energy decreased from 55.49 ± 22.93 rad2 s−3 in the monitoring mode to 15.66 ± 7.29 rad2 s−3 in the active mode. Medians of power reduction were below 60% for the wrist and the elbow. In addition to supplying new information on the interactions between kinematics, dynamics and tremor genesis, this non-invasive technique is an alternative to current therapies. This new approach will provide new insights into the understanding of motor control.

Transcranial magnetic stimulation

In this Primer we have been able to give only a snapshot of the basic features and the applications of TMS. Some fundamentals of the use of TMS are falling into place as we learn more about the effects of different combinations of stimulus intensity, frequency, task and behavioural state. We have not had space to cover some important areas, such as studies of depression, language, eye movements and basic motor physiology, but the technique is now used in almost every area of cognitive neuroscience. Areas in which we can expect the next major advances in the use of TMS (and TDCS) include: the combination of TMS with other techniques to investigate causal interactions between cortical areas; the development of new paradigms to change selectively the baseline state of cortical excitation prior to further magnetic stimulation; and the incorporation of TMS into neuro-rehabilitation programmes.

Introduction: The Use of Animal Research in Developing Treatments for Human Motor Disorders: Brain-Computer Interfaces and the Regeneration of Damaged Brain Circuits

This issue of the ILAR Journal is devoted to animal models of human movement disorders. It is not possible to cover this vast topic in a few short articles, but we hope that the contributing researchers’ descriptions of research models and results will inform, guide, and promote further research on motor disorders. The research field is broad because so much of the nervous system relates to motor function. It is sometimes said that animals have brains because they move faster than plants. Being able to move about clearly puts a premium on having a large brain that can analyze and use both previous experience and ongoing sensory information in order to guide and control motor systems and thus produce skillful and productive behaviors. For humans in particular, our large, complex brains allow a range of skilled performances that greatly exceeds that of any other mammal. We can especially marvel at the performance of our most accomplished musicians and athletes. The ability to develop these skills, which frequently require years of devoted, specialized practice, indicates that general-purpose brain circuits can be rewired through use in order to perfect a variety of specific motor feats. This same flexibility in the use of brain circuits enables us to compensate to various extents for brain injuries, and thereby maintain capabilities as brain impairments progress or recover capabilities lost after injuries. Animal research that is relevant to the treatment of human motor disorders is of several types:

Serotonin Involvement in the Basal Ganglia Pathophysiology: Could the 5-HT2C Receptor be a New Target for Therapeutic Strategies?

The basal ganglia are a highly interconnected group of subcortical nuclei in the vertebrate brain that play a critical role not only in the control of movements but also in some cognitive and behavioral functions. Several recent studies have emphasized that serotonergic pathways in the central nervous system (CNS) are intimately involved in the modulation of the basal ganglia and in the pathophysiology of human involuntary movement disorders. These observations are supported by anatomical evidence demonstrating large serotonergic innervation of the basal ganglia. In fact, serotonergic terminals have been reported to make synaptic contacts with dopamine (DA)-containing neurons and gamma-aminobutyric acid (GABA)-containing neurons in the striatum, globus pallidus, subthalamus and substantia nigra. These brain areas contain the highest concentration of serotonin (5-HT), with the substantia nigra pars reticulata receiving the greatest input. Furthermore, in these structures a high expression of 5-HT different receptor subtypes has been revealed. In this paper, evidence demonstrating the serotonergic control of basal ganglia functions will be reviewed, focusing on the role of the 5-HT2C receptor subtype. In addition, the involvement of 5-HT2C receptors in neurological disorders such as Parkinson's disease and other related motor disorders, and their management with drugs blocking the 5-HT2C receptor will be discussed.