The Basal Ganglia and Adaptive Motor Control

Striatal Plasticity and Basal Ganglia Circuit Function

Redefining Bradykinesia.

Recent transcranial magnetic stimulation studies have shown that the motor output pathway shows a profound inhibition during the preparation of an action. This phenomenon, called “preparatory inhibition”, remains incompletely understood, as it is still unclear which neural structures support it and what function it exactly serves during action preparation. In the current study, we tested this preparatory inhibition in Parkinson’s disease (PD) patients and matched healthy control subjects. The aim was to better understand the role of basal ganglia (which are dysfunctional in PD) and the influence of dopamine replacement therapy on motor inhibition during action preparation.

Oscillations in the Basal Ganglia: The Good, the Bad, and the Unexpected.- Participation of Striatal Neurons in Large-Scale Oscillatory Networks.- Do Local Field Potentials Reflect Synchronized Spiking Activity of Neuronal Populations in the Basal Ganglia? Studies in a Rodent Model of Parkinson's Disease.- A Partial Spectra Method for Predicting Spike Correlations from Local Field Potentials: Application to MPTP Induced Synchronization.- Propagation of Cortical Paroxysms in Basal Ganglia Circuits During Absence Seizures.- Limitations of the Isolated GP-STN Network.- Convergence and Plasticity of Inputs to Striatal Cholinergic Interneurons: The Generation of Synchronised Pauses.- Short and Long-Term Modulation of Synaptic Activity in Striatal Cholinergic Interneurons.- Striatal Acetylcholine Control of Reward-Related Dopamine Signalling.- Changes of Glutamatergic Control of Striatal Acetylcholine Release in Experimental Parkinsonism.- Peptidergic Regulation of Cholinergic Transmission in the Dorsal Striatum: Peptides and Acetylcholine in the Striatum.- Localization and Functions of Kainate Receptors in the Rat Globus Pallidus.- Oligomerization of Dopamine D1 and Glutamate NMDA Receptors: A New Mechanism Regulating Striatal Function.- Modulatory Role of NK1 Receptors in the Basal Ganglia. Studies in NK1-/- Mice.- Trace Amines Cause More than One Effect on Dopaminergic Neurons.- Regulation of Dopamine Release and Dopamine Cell Activity by Endogenous H2O2: Implications for Basal Ganglia Function.- Nociceptin/Orphanin FQ Modulates Neurotransmitter Release in the Substantia Nigra: Biochemical and Behavioural Outcome.- Motor Learning-Related Gene Regulation in the Striatum: Effects of Cocaine.- Opposing Short-Term and Long-Term Effects of Amphetamine Sensitization on Operant Responding For a Food Reinforcer.- Anterograde Trophic Mechanisms Participate in Pattern Formation in the Striatum: A Role For BDNF in Glutamatergic Afferents.- Developmental Assembly of GABA Receptors in the Rat Substantia Nigra.- High Frequency Stimulation of the Subthalamic Nucleus: Electrophysiological and Neurochemical Aspects.- Downregulation of a Metabotropic Glutamate Receptor in Parkinsonian Basal Ganglia.- Pitx3 is Necessary for Survival of Midbrain Dopaminergic Neuron Subsets Relevant to Parkinson's Disease.- D1-Dopamine Receptor Supersensitivity in the Dopamine-Depleted Striatum Involves a Novel Activation of Erk1/2.- Do Systemically Administered Glutamate Antagonists Affect Subthalamic Nucleus Activity? Relevance to Pharmacotherapy of Parkinson's Disease.- Striatopallidal Changes in Early Parkinson's Disease: Partial Dopamine Depletions.- Dynamic Models of Basal Ganglia Function and Parkinson's Disease.- Striatal Grafts and Synaptic Plasticity.- Spontaneous Formation of Lewy Bodies in a Rodent.- Intralaminar Thalamic Nuclei are Main Regulators of Basal Ganglia Possible Involvement in the Pathophysiology of Parkinson's Disease.- Activated Microglia Persist in the Substantia Nigra of a Chronic MPTP Mouse Model of Parkinson's Disease.- Early Behavioral Phenotypes in Mouse Models of Huntington's and Parkinson's Diseases.- Synaptic Alterations in Genetic Mouse Models of Huntington's and Parkinson's Diseases: Is there a Common Thread?.- Changes in the Expression of Tonic and Phasic Neurochemical Markers of Activity in a Rat Model of L-DOPA Induced Dyskinesia.- Bilateral Somatosensory Responses of Pallidal Neurons in Humans Studied with Microrecording.- Alterations in Globus Pallidus Internus Firing Patterns are Associated with Different Movement Disorders.- Biochemical Markers of DBS-Induced Transition from Off to On State in Parkinsonian Patients.- Effect of Deep Brain Stimulation on Tremor.- Thalamic and Cortical Changes in Parkinsonian Disorders.- Neurogenesis in the Basal Ganglia in Huntington's Disease in the Human Brain and in an Animal Model.- The Ventral/Dorsal Divide: To Integrate or Separate.- Feedforward and Feedback Inhibition in the Neostriatum.- Dopaminergic Modulation of Cortical and Striatal Up States.- Integration of Cortical Activity by Striatal Medium Spiny Neurons.- Activation of NOS Interneurones in Striatum after Excitotoxic Lesions of Rat Globus Pallidus.- Electrical Synapses between Output Neurones of the Striatum and Between Neurones of the Substantia Nigra Pars Compacta.- Nitric Oxide Signaling Modulates the Responsiveness of Striatal.- Medium Spiny Neurons to Electrical Stimulation of the Substantia Nigra: Striatal Nitrergic Signaling.- Chandelier Neuron Cartridges in the Rat Prefrontal Cortex Contact Pyramidal Neurons Which Project to the Nucleus Accumbens.- The Pedunculopontine and Reinforcement.- The Pedunculopontine Nucleus: Towards a Functional Integration with the Basal Ganglia.- Glutamatergic and GABAergic Control of Pallidal Activity in Monkeys.- Combined Modeling and Extracellular Recording Studies of Up and Down Transitions of Neurons in Awake or Behaving Monkeys.- Sequential Motor Behavior and the Basal Ganglia: Evidence from a Serial Reaction Time Task in Monkeys.- GABAergic and Dopaminergic Modulation of Basal Ganglia Output in Primates.- The Basal Ganglia-Thalamocortical Circuit Originating in the Ventral Premotor Area (PMv) of the Macaque Monkey.- The Subthalamic Region of the Sheep.- Differential Localization of Vesicular Glutamate Transporters 1 and 2 in the Rat Striatum.- Local Connectivity Between Neurons of the Rat Globus Pallidus.- AUTHOR INDEX.- SUBJECT INDEX

Cognitive deficits in animal models of basal ganglia disorders

Benefits of intensive speech treatment have been documented for a range of speech signs in English speakers with Parkinson's Disease (PD). However, the answer to a critical question that whether the same treatment benefits speech variables including intelligibility in Mandarin speakers is still unclear. In order to develop a targeted speech treatment for Mandarin speakers with PD, we reviewed the efficacy of intensive speech treatment to improve vocal loudness and functional communication and discuss possible explanations for efficacy on Mandarin speakers with PD. Literatures about intensive speech treatment for Mandarin speakers with PD were retrieved from PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Wanfang and Weipu Database for Chinese Technical Periodicals (VIP) Database. Search strategy was (voice therapy OR speech therapy OR voice treatment OR speech treatment OR voice training OR speech training OR voice rehabilitation OR speech rehabilitation OR Lee Silverman voice treatment OR intensive speech treatment) and (Parkinson's disease) and (Mandarin speakers OR Chinese OR Chinese people). Five randomized controlled trials were selected and possible explanations for efficacy on individuals with PD are discussed. Further research directions are suggested. The existing evidence from treatment efficacy studies of intensive speech treatment provides support for improving vocal loudness, speech intelligibility, pitch and rate in Mandarin speakers with PD. Our future research will continue to work to conduct a large sample multicenter randomized controlled trial to provide high quality evidence and understand the basic mechanisms accompanying treatment-related change.

Aim: Individuals with Alzheimer disease (AD), Huntington disease (HD) and Parkinson disease (PD) have impaired balance, and comparing these deficits could improve management of neurological diseases.Methods: Scores on the Balance Evaluation Systems Test (BESTest) were compared across three groups, consisting of individuals with AD, HD and PD in early stages of their respective disease.Results: Individuals with PD had significantly higher scores on the BESTest than individuals with AD (95% CI [4.30, 21.37], p<0.01) or HD (95% CI [6.53, 24.18], p<0.001). Individuals with AD and HD were not significantly different on the overall BESTest or any of its subsections.Conclusion: AD and HD may have overlapping pathologies resulting in early and similar balance impairments in these groups.

Huntingtons disease treatments In 1872, George Huntington, an American physician who at the time was only 22 years old, published a short communication in the "Medical and Surgical Reporter" (Philadelphia) describing a hereditary form of chorea (uncontrollable dance-like movements similar to St. Vitus dance). As a young boy, George had accompanied his father in his visits to families in East Hampton, New York, who were affected by the dreaded disease and noticed that if the parents presented with the disease, their progeny had a great chance of acquiring it. These observations led him to write the above-noted first description of the disease, which ultimately was named after him. In 1993, the gene mutation causing Huntington's disease (HD) was discovered thanks to the impetus of Dr. Nancy Wexler (Columbia University) and collaborators.1 It consists of an elongation of CAG (coding for glutamine) repeats in a previously unknown gene located in the short arm of chromosome 4. When the number of CAG repeats exceeds 39, the disease will inexorably occur at some point in life. HD is a devastating, incurable neurodegenerative disease. Its prevalence is relatively high in Western European nations, Venezuela, the United States, Canada, and Oceania (5-10/100 000) but very low in Asian and most African countries (0.1-0.5/100 000). Although victims of the disease are thus relatively rare, the number of people at risk is significantly higher, emphasizing the need for finding new treatments to alleviate symptoms and improve the quality of life for patients suffering from HD. The hallmark histopathology of HD is cell degeneration in striatum and cerebral cortex, which explains the emergence of motor (chorea), cognitive, and psychiatric symptoms. The probable causes of cell death are still unknown, but significant strides have been made in the past few years to understand disease mechanisms. Such advances have been made possible in part by the generation of genetic animal models of HD. Before the advent of such models, excitotoxic models (eg, intrastriatal injection of quinolinic acid) were the only tools for mechanistic studies and were based on the idea that excessive glutamate release from corticostriatal terminals or heightened sensitivity of glutamate receptors in striatal neurons was the principal cause of cell death.2 The excitotoxic models, although certainly possessing some heuristic value, proved to be simplistic and to have important shortcomings, notably in that they did not allow examination of disease progression. Although also imperfect, genetic animal models have provided a vast number of mechanistic insights and have emphasized the fact that functional alterations, more than cell death, can explain a variety of HD symptoms.3 In particular, synaptic disconnection and miscommunication between basal ganglia structures and the cerebral cortex appear to play a crucial role. The R6/2 transgenic mouse model, created in the laboratory of Dr. Gillian Bates (then at King's College London) just 3 years after the discovery of the gene mutation,4 has been instrumental in the exploration of new therapies for HD and the gold standard for drug testing. Since then, numerous animal models have been created that allowed further insights into disease mechanisms and progression. Although no model can reproduce yet the whole gamut of human HD symptoms, animal models represent an invaluable source of knowledge and probably the only way to develop a real cure. The present Special Issue (SI) on HD is a small compendium of recent advances arising from the utilization of animal and cellular models for better understanding of disease mechanisms and for discovering new potential treatments. The authors are well-renowned leaders in their respective fields, and each one has provided either original data or detailed reviews. The 9 articles included in this issue can be considered a snapshot of the current status of HD research using those models. In no way does it aim to be a comprehensive overview of the vast amount of research presently being conducted in the HD field. However, we hope that this SI will attract the attention of investigators working on HD and other neurodegenerative diseases that may share common mechanisms. Although the functions of the normal huntingtin protein are still unclear, there is substantial evidence that, among others, it plays a key role in proper brain development, transcriptional regulation, vesicle transport, and synaptic transmission.5, 6 From a systems perspective, it is of great interest that communication along the cortico-basal ganglia-thalamocortical loop is disrupted, lending support to the idea that HD is, above all, a synaptopathy.7 Disrupted connectivity is best exemplified in Anton Reiner's (University of Tennessee) review examining striatal neuron inputs and outputs in HD8 (pp. 250–280). Professor Reiner is a world-renowned authority in the field of HD and one of the discoverers of the increased vulnerability of enkephalin-containing striatal projection neurons (SPNs) constituting the indirect pathway. In particular, he is interested in anatomical changes occurring in patients and in animal models during HD progression. In his detailed review, Professor Reiner dissects the topography and chronology of connectivity changes occurring in HD. From early loss of cortical and thalamic inputs to striatum to late disruption of direct pathway SPNs, he is able to explain the changing patterns of motor dysfunction in HD patients. Abnormalities in glutamate release and/or glutamate receptor sensitivity have long been invoked to explain striatal cell death in HD. Although probably not exclusive, anatomical and physiological data support glutamate involvement. George Rebec (Indiana University) has been studying corticostriatal communication and how glutamate transport in the corticostriatal pathway is altered in HD animal models9 (pp. 281–291). Using a wide array of techniques including in vivo electrophysiological recordings, measurement of glutamate release, and computational modeling Professor Rebec and his team have demonstrated important changes in striatal and cortical neuron firing patterns, as well as dysregulation of dynamic changes in extracellular glutamate and ascorbate. By demonstrating deficits in astrocyte-mediated glutamate transport in the striatum, he has paved the way for new ideas to treat HD. He has shown that increased expression of glutamate transport proteins restores glutamate and ascorbate homeostasis in striatum while normalizing striatal neuronal activity and improving behavioral signs. However, in HD not only glutamate transmission goes awry. Dysregulation of glutamate release along the corticostriatal pathway triggers compensatory mechanisms to prevent cell damage. The function of GABA, the main inhibitory neurotransmitter in the brain, also is altered in HD. Upregulation of phasic GABA release in striatum, as well as deficits in tonic GABA, has been demonstrated in mouse models. Maurice Garret (Université de Bordeaux) is an expert on GABA receptor structure and function in the brain. Recently, he has focused his attention on uncovering alterations of GABA receptors in animal models. He demonstrated, beyond doubt, that glutamate and dopamine are not the only neurotransmitters affected by the malady, as the GABA system also is deeply altered. In addition, GABA is the main neurotransmitter used by SPNs of both direct and indirect pathways. Thus, any changes in GABA function occurring in striatum will have an effect on key output regions including the external globus pallidus and the substantia nigra pars reticulata. In his insightful review10 (pp. 292–300), Dr. Garret examines specific changes in GABAA receptor subunits in different basal ganglia regions and highlights potential therapeutic avenues by targeting selective GABAA receptor subunits to treat nonmotor symptoms such as sleep disturbances commonly observed in HD. The laboratory of Lynn Raymond (University of British Columbia, Vancouver) is well known for its contributions to our understanding of the role that glutamate extrasynaptic NMDA receptors play in excitotoxicity. Deleterious effects are likely mediated by dysregulation of calcium influx and handling in different cell compartments. Dr. Raymond and her collaborators James P. Mackay and Wissam B. Nassrallah discuss how abnormal calcium handling can lead to neuronal degeneration11 (pp. 301–310). As many alterations observed in HD animal models occur very early in development, they wonder whether changes are a primary cause or the result of compensatory mechanisms. This is a provocative idea emphasizing the capabilities of the brain to repair itself. Their review also highlights possible therapies focused on restoring calcium homeostasis. Calcium influx, either via NMDA receptors or voltage-gated and store-operated channels, is not the only process affected in HD. Potassium channels also play an important role as they are involved in myriad of cellular processes, most of them designed to prevent neuronal hyperexcitability. Potassium channel dysfunction was first suspected by studies showing that SPNs are more depolarized in HD mouse models, pointing to decreased inward rectification due to loss of Kir channel expression. Working in Baljit Khakh's laboratory (University of California Los Angeles), Xiaoping Tong (presently a Professor at Shanghai Jiao Tong University School of Medicine) discovered that astrocytic Kir4.1 channels were deficient in HD mouse models. This deficit was accompanied by increased extracellular potassium, which in turn could explain depolarized resting membrane potentials of affected SPNs. Further, upregulation of Kir4.1 channels ameliorated the HD phenotype. In their contribution to the SI12 (pp. 311–318), Professor Tong and collaborators review evidence summarizing recent progress on the function of neuronal and astrocytic potassium channels and their involvement in HD pathology using animal models. They also illustrate how targeting potassium channels can be used for the treatment of HD. The altered interplay between neurotransmitters and channels explains many of the molecular cascades leading to neurodegeneration in HD. But this is not, by any stretch of the imagination, the whole story. Cellular energy metabolism is deeply disturbed in HD. In particular, inefficient use of lactate by HD neurons contributes to metabolic failure. Maité A. Castro (Universidad Austral de Chile), an expert in cellular energy metabolism, and colleagues demonstrate that HD cells exhibit decreased expression of the neuronal glucose transporter GLUT3, which could be the cause of insufficient energy supply13 (pp. 343–352). Further, stimulation of lactate uptake by ascorbic acid could be restored by overexpressing GLUT3. Again this opens new avenues for HD treatment. Another potential avenue targets transcriptional dysregulation, a major cause of HD pathology. Francesca Fusco (Fondazione Santa Lucia, Rome) and Antonella Cardinale review recent neuroprotective strategies via phosphodiesterase (PDE) inhibition and consequent upregulation of cyclic nucleotide signaling in HD14 (pp. 319–328). They argue that, since mutant huntingtin alters cAMP response element-binding protein (CREB), which in turn promotes transcription of brain-derived neurotrophic factor (BDNF), strategies aimed at increasing CREB transcription could have neuroprotective effects in HD animals. As PDEs are enzymes that catabolize cAMP and/or cGMP in the cell, their inhibition could be beneficial. Also highlighting the beneficial effects of neurotrophic factors, Elizabeth Hernández-Echeagaray (Universidad Nacional Autónoma de México) and colleagues examine the role of neurotrophin-3 (NT-3) in neuroprotection and synaptic plasticity in the striatum of an animal model of HD15 (pp. 353–363). They convincingly demonstrate that normal synaptic plasticity in the corticostriatal pathway is aberrant in HD model mice but it can be restored by administration of NT-3. One of the most challenging aspects of HD research relating to therapies is whether cell loss can be prevented or cells can be replaced. In human HD and, to a lesser degree, in genetic animal models, striatal and cortical cell loss is massive. Fortunately, regenerative medicine is becoming a reality and specific cell types may be able to be replaced using stem cells that can be induced to adopt particular phenotypes. Recent studies demonstrate that cells implanted in the brain of HD model mice can survive and differentiate. Notably, most studies demonstrate clear benefits on HD symptoms with some showing a possible mechanism of action that includes the release of neurotrophic factors such as BDNF. Sandra M. Holley (University of California Los Angeles, UCLA), working in the Cepeda-Levine laboratory, and associates at the University of California Davis (UCD) and at the University of California Irvine (UCI) review the use of stem cells in HD animal models16 (pp. 329–342). In their California Institute for Regenerative Medicine (CIRM)-funded studies, they showed that human-derived neural stem cells implanted in HD mice can protect or repair damaged tissue, delay disease progression, decrease pathologies, and increase production of neurotrophic molecules. In this SI, they also provide a more detailed electrophysiological characterization of human-derived neural stem cells implanted in HD mice. We would like to thank all the contributors who took time from their busy schedules to write comprehensive reviews or high-quality original papers that will certainly help the neuroscience community in general and the HD field in particular. Finally, we would like to thank CNSNT and its Editor-in-Chief, Ding-Feng Su, as well as its Managing Editor, Buddy Zhou, for encouraging the compilation of this SI on HD. Without their input and guidance, this SI would not have been possible.

The basal ganglia are key structures for motor, cognitive and behavioral functions. They undergo several changes with aging and disease, such as Parkinson's or Huntington's disease, for example. Iron accumulation in basal ganglia is often related to these diseases, which is conventionally monitored by the transverse relaxation rate (R2 *). Quantitative susceptibility mapping (QSM) is a novel contrast mechanism in MRI produced by adding information taken from the phase of the MR signal to its magnitude. It has been shown to be more sensitive to subtle changes in Parkinson's disease. In order to be applied widely to various pathologies, its reproducibility must be evaluated in order to assess intra-subject variability and to disseminate into clinical and pharmaceutical studies. In this work, we studied the reproducibility and sensitivity of several QSM techniques. Fourteen subjects were scanned four times, and QSM and R2 * images were reconstructed and registered. An atlas of the basal ganglia was used to automatically define regions of interest. We found that QSM measurements are indeed reproducible in the basal ganglia of healthy subjects and can be widely used as a replacement for R2 * mapping in iron-rich regions. This reproducibility study could lead to several lines of research in relaxometry and susceptibility measurements, in vivo iron load evaluation as well as pharmacological assessment and biomarker development. Copyright © 2016 John Wiley & Sons, Ltd.

Current knowledge is summarized about long-term memory systems of the human brain, with memory systems defined as specific neural networks that support specific mnemonic processes. The summary integrates convergent evidence from neuropsychological studies of patients with brain lesions and from functional neuroimaging studies using positron emission tomography (PET) or functional magnetic resonance imaging (fMRI). Evidence is reviewed about the specific roles of hippocampal and parahippocampal regions, the amygdala, the basal ganglia, and various neocortical areas in declarative memory. Evidence is also reviewed about which brain regions mediate specific kinds of procedural memory, including sensorimotor, perceptual, and cognitive skill learning; perceptual and conceptual repetition priming; and several forms of conditioning. Findings are discussed in terms of the functional neural architecture of normal memory, age-related changes in memory performance, and neurological conditions that affect memory such as amnesia. Alzheimer's disease, Parkinson's disease, and Huntington's disease.

BackgroundThe semiology and determinants of apathy are largely unknown across amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Huntington’s disease (HD), due to both motor and non-motor confounders. This study thus aimed at (1) profiling apathy in ALS, PD, and HD and (2) exploring its clinical determinants.MaterialsConsecutive ALS (N = 99), PD (N = 73), and HD (N = 25) patients underwent a motor-free assessment of apathy (Dimensional Apathy Scale, DAS), global cognition, anxiety and depression. Function was assessed through disease-specific scales. The DAS was also completed by N = 101 healthy controls (HCs). Between-group comparisons on DAS scores were implemented by covarying for all applicable confounders. Predictive models on DAS scores were built through multiple, stepwise regressions.ResultsParkinson’s disease and HD, but not ALS, patients were more apathetic than HCs—with HD patients also selectively showing lower initiation and poorer goal-directed planning than HCs. Higher apathetic features were detected in PD and HD as compared to ALS. Education was a protective factor against apathy in ALS. Anxiety was a risk factor for global apathy in ALS, HD, and to a lesser extent, in PD, whereas, protective only toward affective disintegration in PD and ALS. Cognitive inefficiency was a risk factor toward apathy in both PD and ALS. Depression was a risk factor for executive-related apathy in PD.DiscussionThis study provides unprecedented insights into the heterogeneous semiology and determinants of apathy across ALS, PD, and HD via the DAS, in turn informing clinical practice and research.

Twenty-three patients with Wilson's disease (WD) treated with D-penicillamine underwent clinical examination, as well as laboratory and motor testing. The clinical findings were scored. Laboratory tests included determination of the caeruloplasmin level, the free serum copper level, 24 h urinary copper excretion, liver enzymes and in 10 patients liver copper content of a liver biopsy. Laboratory tests and clinical scores were correlated. To quantify impairment of voluntary movements in WD fastest possible isometric index finger extensions and fastest alternating finger movements were analysed. Eleven patients presented with abnormally slow and 15 with abnormally irregular voluntary movements. Slowness of alternating movements correlated with the clinical score. The clinical score also correlated with the duration of symptoms prior to onset of therapy. Motor testing turned out to be sensitive enough to monitor improvement of neurological symptoms after onset of therapy. Comparison with motor testing in other basal ganglia diseases and cerebellar patients showed differences to patients with Parkinson's and Huntington's disease and similarities to patients suffering from AIDS-related dementia. In a small number of WD-patients similar results as in patients with a degenerative cerebellar disease were found.

Huntington disease (HD) is a neurodegenerative disorder caused by an expansion of polyglutamines in the first exon of huntingtin (HTT), which confers aggregation-promoting properties to amino-terminal fragments of the protein (N-HTT). Mutant N-HTT aggregates are enriched for ubiquitin and contain ubiquitin E3 ligases, thus suggesting a role for ubiquitination in aggregate formation. Here, we report that tumor necrosis factor receptor-associated factor 6 (TRAF6) binds to WT and polyQ-expanded N-HTT in vitro as well as to endogenous full-length proteins in mouse and human brain in vivo. Endogenous TRAF6 is recruited to cellular inclusions formed by mutant N-HTT. Transient overexpression of TRAF6 promotes WT and mutant N-HTT atypical ubiquitination with Lys6, Lys27, and Lys29 linkage formation. Both interaction and ubiquitination seem to be independent from polyQ length. In cultured cells, TRAF6 enhances mutant N-HTT aggregate formation, whereas it has no effect on WT N-HTT protein localization. Mutant N-HTT inclusions are enriched for ubiquitin staining only when TRAF6 and Lys6, Lys27, and Lys29 ubiquitin mutants are expressed. Finally, we show that TRAF6 is up-regulated in post-mortem brains from HD patients where it is found in the insoluble fraction. These results suggest that TRAF6 atypical ubiquitination warrants investigation in HD pathogenesis.

Malfunction of the basal ganglia leads to movement disorders such as Parkinson's disease, dystonia, Huntington's disease, dyskinesia, and hemiballism, but their underlying pathophysiology is still subject to debate. To understand their pathophysiology in a unified manner, we propose the "dynamic activity model", on the basis of alterations of cortically induced responses in individual nuclei of the basal ganglia. In the normal state, electric stimulation in the motor cortex, mimicking cortical activity during initiation of voluntary movements, evokes a triphasic response consisting of early excitation, inhibition, and late excitation in the output stations of the basal ganglia of monkeys, rodents, and humans. Among three components, cortically induced inhibition, which is mediated by the direct pathway, releases an appropriate movement at an appropriate time by disinhibiting thalamic and cortical activity, whereas early and late excitation, which is mediated by the hyperdirect and indirect pathways, resets on-going cortical activity and stops movements, respectively. Cortically induced triphasic response patterns are systematically altered in various movement disorder models and could well explain the pathophysiology of their motor symptoms. In monkey and mouse models of Parkinson's disease, cortically induced inhibition is reduced and prevents the release of movements, resulting in akinesia/bradykinesia. On the other hand, in a mouse model of dystonia, cortically induced inhibition is enhanced and releases unintended movements, inducing involuntary muscle contractions. Moreover, after blocking the subthalamic nucleus activity in a monkey model of Parkinson's disease, cortically induced inhibition is recovered and enables voluntary movements, explaining the underlying mechanism of stereotactic surgery to ameliorate parkinsonian motor signs. The "dynamic activity model" gives us a more comprehensive view of the pathophysiology underlying motor symptoms of movement disorders and clues for their novel therapies.

The pattern of neurodegeneration in Huntington's disease: a comparative study of cannabinoid, dopamine, adenosine and GABA A receptor alterations in the human basal ganglia in Huntington's disease