Tremor is the most common movement disorder phenomenology. Tremor disorders are classified based on the predominant tremor characteristics. Essential tremor (ET) is characterized by action tremor in the upper extremities, whereas Parkinson’s disease (PD) tremor classically presents as tremor at rest. Dystonic tremor (DT) is less rhythmic and is usually associated with sustained muscle twisting.1,2 Other tremor disorders, including cerebellar outflow tremor, Holmes tremor, and orthostatic tremor, are relatively rare. Despite some clinical heterogeneity, one of the important aspects of tremor disorders is the overlapping clinical features. For example, severe ET patients can develop rest tremor, and severe PD patients can have action tremor.3 Many ET cases also have a dystonic component.4 While tremor disorders are likely to be heterogeneous groups of diseases with phenotypical overlaps, the brain circuitry preferentially involved in the generation of a specific type of tremor (action vs. rest vs. dystonic) is likely to share some commonalities with additional modulatory components. Therefore, studies of animal models with different types of tremor will likely lead to a comprehensive understanding of the mechanism of diverse yet overlapping clinical features of tremor.
Based on neuroimaging studies5–7 and pathological studies8,9 in patients, the cerebellum is involved in tremor generation. In addition, magnetoencephalography and high-density electroencephalography have shown that brain areas interconnected with the cerebellum or further downstream regions, including the thalamus, motor and pre-motor cortex, and part of the brainstem, may affect tremor expression.6,10 However, the mechanism by which structural alterations within the brain circuit generate tremor remains unclear. Similarly, the oscillatory neuronal activities are thought to be the physiological correlates for tremor.11,12 Yet, it is unclear how the brain circuitry alterations generate these rhythmic neuronal activities to drive tremor. Thus, animal models are a useful tool to assess the relationship between structural brain alterations, altered neuronal physiology, and tremor. In addition, animal models of tremor may be a platform for therapy development. Note that tremor is a terminology for movement disorder that describes involuntary, rhythmic movements; therefore, tremor is a symptom, rather than a disease. Thus, animal models of tremor capture the symptoms of a disease, rather than reflect the biological processes underlying the disease.
The present paper will first review the validated tremor animal models with detailed clinical features (action tremor vs. rest tremor) and the pharmacological responses of tremor in these models using frequency-based measurement rather than merely visual observation. We will also briefly review other animal models of tremor with varied results. We will discuss how the pathophysiology learned from animal models of tremor can help us to understand the controversies of phenotypical overlaps of tremor disorders. Finally, we will attempt to apply the knowledge of tremor pathophysiology learned from animal models to explain some of the controversies in the tremor research field.
A PubMed search was conducted in May 2018 using the term “tremor” in combination with the following search terms: “animal models”, “mouse”, “rat”, “monkey”. In the initial screening, we identified 1,171 articles; of these, 64 and 1,039 articles that were not written in English and/or were irrelevant to the topic of this review, respectively, were disregarded. Therefore, we selected 68 of the remaining articles for this review. An additional five articles were included based on the references. Thus, a total of 73 articles were selected for this review (Table 1, Figure 1).
|Key Words and Combination||Number of Publications|
|Tremor AND Animal models||Total||Included||Excluded|
|Tremor AND mouse||194||12||182 (not in English, 9; not relevant, 173)|
|Tremor AND rat||413||37||376 (not in English, 15; not relevant, 361)|
|Tremor AND monkey||470||15||455 (not in English, 31; not relevant, 424)|
|Total number of articles included for review||94||4||90 (not in English, 9; not relevant, 81)|
|Total number of articles included from the references of the including articles||68|
|Final number of articles included for review||5|
Based on the search results, we will first discuss the most widely studied animal models for action tremor (harmaline-induced rodent models) and rest tremor (dopamine-depleted monkey models) with defined tremor frequency and characteristic measurement. We will next discuss the animal models of tremor with frequency measurement but no detailed action vs. rest tremor description. We will also review the current literature for animal models of tremor without objective tremor measurement; therefore, whether there is true tremor present in these animal models will require further investigation. We will also review the tremor pathophysiology in these animal models and how this knowledge should advance our understanding of human tremor disorders.
The classical animal model of action tremor is the harmaline-induced model.13 A single dose of harmaline can induce action tremor by enhancing the coupling between the inferior olivary (IO) neurons.14–17 The IO neurons have intrinsic subthreshold membrane potential oscillations at 1–10 Hz, and harmaline exposure can result in enhanced communications between IO neurons, which entrain the downstream Purkinje cells (PCs) to fire synchronously and rhythmically at around 10–16 Hz via axons of the IO neurons called climbing fibers (CFs).14,15 Animals exposed to harmaline develop tremor at the same frequency.16,17 During the tremor state, PCs fire rhythmic complex spikes, which originate from CF excitatory synaptic transmission onto PCs with a dramatic suppression of simple spikes.15,18 Therefore, harmaline is thought to enhance the CF–PC synaptic transmission, which is intrinsically oscillatory, to drive tremor.
Harmaline-induced tremor is predominantly action tremor13 (Figure 2) that responds to propranolol, primidone, and alcohol.19 Therefore, harmaline-induced tremor has long been postulated to be an animal model of ET. Harmaline belongs to a group of naturally occurring compounds, called β-alkaloids. In ET patient blood and brain, increased harmaline-related β-alkaloids, such as harmane, have been observed,20,21 suggesting that environmental factors may contribute to oscillatory activities in the olivocerebellar system in ET patients.
Under the conceptual framework of oscillatory neuronal activities in tremor, several modulatory agents that can influence the olivocerebellum have been tested in this harmaline-induced tremor model as pre-clinical studies for ET. For example, a gap junction blocker, carbenoxolone, has been shown to effectively suppress harmaline-induced tremor22 and T-type calcium channels that are important for PC complex spikes can also suppress harmaline-induced tremor.23 Currently, a phase II randomized placebo-controlled clinical trial for a T-type calcium channel blocker is underway for ET (clinicaltrials.gov: NCT03101241), partly based on the understanding of the cerebellar circuitry in harmaline-induced tremor.
While harmaline-induced tremor indicates the importance of the connections between the IO neurons and PCs (Figure 3), animal model studies suggest that other parts of the cerebellar system can also drive oscillatory neuronal activities. For example, the gamma-aminobutyric acid (GABA)-ergic deep cerebellar nuclei (DCN) send axons to IO neurons, which may control the coupling between IO neurons. Loss of this nucleo-olivary GABAergic control may result in enhanced electrotonic coupling between IO neurons, leading to synchronized PC complex spikes.24 Additionally, IO neurons also receive glutamatergic inputs, which may modulate the synchronization of PC firing.25 These regulatory components of the olivo-cerebellar system are likely to determine the frequency and the strength of neuronal synchrony, and potentially influence the presentation of tremor. In a post-mortem study of ET patients, there was no evidence of IO neuronal loss,26 which might have allowed the olivocerebellum system to generate rhythmic and synchronized neuronal activities, under the regulation of the above-mentioned nucleo-olivary control, to drive tremor. Whether ET patients exhibit alterations of these synaptic structures in IOs requires further investigation.
Harmaline has been shown to induce action tremor in a wide variety of animals, including mice,19,22,27 rats,19 cats,15 monkeys,28 and pigs,29 suggesting an evolutionarily conserved olivocerebellar circuit for tremor generation. However, different species may have different frequencies in harmaline-induced tremor (mice, 10–16 Hz; rats, 8–12 Hz; pigs, 8–12 Hz).19 Note that ET patients have tremor at 4–12 Hz.11 Interestingly, the chronic responses to harmaline also differ among species. Repeated exposures to harmaline will induce “tolerance” in rats and pigs, where the tremor decreases with repeat exposure. This phenomenon presents an exception in mouse models, which tend to develop robust tremor even with repeated harmaline injections.29,30 Neuropathological assessment between rats and mice with repeated harmaline exposures showed that rats have extensive PC loss,31 which may be due to excitotoxicity from overstimulation of CF synaptic transmission onto PCs,31 whereas PCs in mice are relatively preserved.30 These results might indicate that preserved PCs may be required for the continuous harmaline-induced tremor, which is thought to generate from CF-driven synaptic activities. In ET patients, moderate PC loss has also been identified.8,32 Whether the PC loss in ET is due to the longstanding, abnormal excitatory synaptic transmission or is a primary PC degenerative process requires further investigation.
While harmaline-induced action tremor models present similarities to ET, this model remains controversial. First, agents that can worsen ET, such as valproate and lithium, tend to suppress harmaline-induced action tremor;33 however, these tremor-suppressing effects might be due to the non-specific reduction of motor activities because harmaline induces predominantly action tremor. Further studies are required. Second, harmaline is a toxin model and, as such, tremor amplitude may be dose-dependent and further influenced by the timing of tremor assessment. Third, the rapid tolerance of harmaline in animals such as rats and pigs present difficulty for large-scale drug screening. However, the aforementioned animal models still have significant value for the validation of specific agents.
Nonetheless, harmaline-induced action tremor models indicate that the olivocerebellum is capable of generating action tremor and neuronal rhythmicity and synchrony might underlie the pathophysiology of tremor. Along these lines, the structural alterations that can lead to neuronal synchrony and/or rhythmicity within the olivocerebellar circuitry may contribute to tremor. For example, abnormal CF–PC synaptic connections have been identified in post-mortem studies of ET cerebellum. Specifically, CFs form synaptic connections with the distal, spiny branchlets of PC dendrites, which should have been the parallel fiber territory.9,34–37 This CF–PC synaptic pathology distinguishes ET from other cerebellar degenerative disorders.35 Furthermore, this CF–PC synaptic pathology may occur across different subtypes of ET, regardless of age of tremor onset and family history of tremor.9 The extension of CF synapses onto the parallel fiber synaptic territory on PCs is likely to increase the influence of IO activities on PCs, which might enhance the synchrony and rhythmicity in the cerebellar circuitry.38,39 The other source of neuronal synchrony within the cerebellar circuitry may occur at the level of downstream of PC dendritic synapses. For example, PC axonal collaterals and sprouting have been found in post-mortem studies of ET cerebellum,40 possibly in response to partial PC loss. It is possible that this PC axonal sprouting process could set up rhythmicity and synchrony within the cerebellar circuitry. Note that post-mortem studies of human pathology need to be interpreted with caution. In particular, observations in human studies cannot establish whether the structural changes are the consequences of longstanding neuronal activities associated with tremor or the primary causes for tremor. Detailed tremor measurements and physiology studies in animal models with the above-mentioned pathological alterations will likely provide further mechanistic insight.41 In addition, changes in ion channels and/or receptors have not been extensively studied post-mortem in human brains affected by tremor, which might shed light on the pathomechanism of tremor.
In summary, different levels of neuronal synchrony within the cerebellar system are believed to set up the pathophysiological substrate for tremor generation, which may partly explain the clinical heterogeneity of ET.4
Rest tremor is one of the cardinal features of PD. While dopamine neuronal loss in the nigrostriatal system is the pathological hallmark of PD,42 dopamine depletion in animals leads to bradykinesia, with rest tremor not consistently reported in such models.43,44 The most commonly used toxin to deplete dopamine terminals in mice is 6-hydroxydopamine (6-OHDA) injection into the striatum; this procedure can infrequently induce rest tremor.44 Even in mice models with 6-OHDA-induced rest tremor, tremor is usually not a prominent feature. It is currently unknown why some mice develop rest tremor while others don’t. Detailed mechanistic studies are required.
The early work for rest tremor comes from studies in monkeys: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated vervet (African green) monkeys develop robust rest tremor while MPTP-treated rhesus (Macaca mulatta) monkeys have only very infrequent rest tremor.43 The rest tremor in vervet monkeys is approximately 5–7 Hz, measured using an accelerometer, with corresponding synchronous firing of pallidal neurons. This tremor is very similar to that in PD patients.43 Detailed neuropathological studies comparing these two types of MPTP-treated monkeys found that vervet monkeys have more affected dopamine neurons in the retrorubral area, whereas rhesus monkeys have more profound dopamine neuronal loss in the substantia nigra pars compacta.45–47 The retrorubral dopamine system has preferential projection to the pallidum, suggesting that pallidal dopamine might play a role in rest tremor generation,48 which is consistent with recent findings in human functional magnetic resonance imaging (fMRI) studies.7,49 However, there are few studies focusing on the anatomy and functions of the pallidal dopamine pathway, and its role in tremor generation remains largely unknown. Further comparisons of the neuropathology and physiology between animal models will lead to a better understanding of the mechanism of rest tremor.
Recent advancement of knowledge of rest tremor comes from human neuroimaging studies7,49 which demonstrate that the interaction between the basal ganglia and the cerebellum is important for rest tremor generation. Specifically, the “dimmer-switch” model proposes that the basal ganglia initiate tremor whereas the cerebellum modulates tremor amplitude and rhythmicity50 (Figure 3). The involvement of the cerebellum system is further supported by the effectiveness of deep-brain stimulations in the region of the thalamus that receives cerebellar output both in 6-OHDA-treated mice with rest tremor44 and in PD patients.51 Another evidence of the cerebellar involvement in rest tremor is that PD patients have hyper-metabolism in the cerebellum based on the positron emission tomography (PET).52 Whether this hypermetabolism in the cerebellum has a structural basis or merely reflects functional neuronal activities remains to be studied. Intriguingly, a study recently found abnormal CF–PC synaptic organization and other PC pathology in post-mortem brain studies of PD cases with rest tremor,35 which may suggest that structural changes in the cerebellum contribute to rest tremor. The detailed mechanism of how the interaction between the basal ganglia and the cerebellum generates rest tremor requires further studies in animal models to test the causal relationship between structural alterations in the brain circuitry and tremor.
Recently, several quantitative studies of novel animal models have been performed. However, it is unclear whether these animals have predominantly action tremor or rest tremor. Therefore, we have included these animal models and the related pathophysiology in this section.
A recent discovery of tremor of Waddles (wdl) mice, which have spontaneous mutations in the Car8 gene,53 has greatly advanced our understanding of tremor in animal models. CAR8 protein is predominantly expressed in PCs and the loss-of-function mutation of Car8 in wdl mice results in tremor of 5–15 Hz. wdl mice have altered frequency and regularity of simple spike and complex spikes of PCs, which likely underlie the physiology of tremor. Another interesting feature of wdl mice is the disturbance of the microzonal organization of the cerebellum. The cerebellar circuitry has been organized in the microzones, for which there are specific sets of CF–PC–DCN connections that govern motor control.54 The afferent inputs to the cerebellum, mossy fibers, also follow such microzonal rules. The microzones of the cerebellum could be traced by a set of PC markers, such as zebrin II or excitatory amino acid transporter type 4 (EAAT4).55,56 The disturbance of microzonal organization within the cerebellum may cause improper neuronal signaling, leading to tremor. It remains to be studied in detail how this altered PC firing in the context of microzonal organization can lead to tremor in wdl mice. Further post-mortem studies in microzonal organization of tremor disorders using the human brain will test the relevance of such findings in patients. Nonetheless, mutations of Car8 have been found in patients with tremor and ataxia,57,58 which further contribute to the translational aspect of this mouse model and human disorders.
One of the main hypotheses of tremor generation is PC loss,8,32 which may potentially be modeled by the recent identification of the Shaker rat. This natural mutant rat develops low-frequency tremor of around 5 Hz; the predominant pathology of this rat is PC loss, particularly in the anterior lobe of the cerebellum.59 Interestingly, the tremor is present at the stage of mild to moderate PC loss whereas the Shaker rats eventually develop frank ataxia with severe PC loss, indicating that tremor might arise in the intermediate stage of PC degeneration.60 However, if partial PC loss is sufficient to cause tremor, one would expect to observe tremor in the early stage of hereditary ataxias with PC degeneration such as spinocerebellar ataxias (SCAs). However, tremor only occurs in a minor subset of SCA patients.61 Within the common types of SCAs, SCA2 often has tremor when compared with SCA1 and SCA6.61 Therefore, further comparisons of varied subtypes of SCAs with PC degeneration might provide further insight into the pathophysiology of tremor.
Another hypothesis for tremor states that GABA deficiency within the cerebellar circuitry leads to enhanced pacemaking neuronal activities.62 This hypothesis originated from the observation of a subset of ET patients who responded to GABAergic medications, such as primidone and alcohol.63,64 Relevant to this clinical observation, a moderate decrease in GABA receptors has been identified post-mortem in the ET dentate nucleus.65 Along these lines, knockout mice with GABAA receptor α1 subunit deficiency have been found to develop tremor that is responsive to propranolol and primidone.66 However, the detailed physiological alterations in dentate neurons and PCs in the freely moving GABAA receptor α1 subunit knockout mice still need to be determined, and whether this mouse model has predominant rest or action tremor requires further investigation. The aforementioned mouse model has some unique characteristics that are distinct from those of ET patients. First, diazepam, a medication than may lessen tremor in ET patients,63 can dramatically enhance tremor in this mouse model. The GABAA receptor α1 subunit knockout mice have a 15–19 Hz tremor,66 which is at a significantly higher frequency than that in ET patients.11 Third, a recent neuroimaging finding showed that ET patients do not have obvious GABA deficiency in the dentate nucleus,67 which questions the relevance of this mouse model to ET in humans. Another possibility is that GABA deficiency in ET patients occurs outside the dentate nucleus, such as in the thalamic nucleus68 or IO neurons,24 which might cause oscillatory neuronal activities and tremor. Alcohol responsiveness remains a phenomenon of interest in studies of ET. While this mouse model does not possess the GABAA receptor α1 subunit, mouse tremor can be suppressed by alcohol, indicating that an alternative factor, such as different subtypes of GABA receptors, might be responsible for this tremor-suppression effect. Future studies on the neuronal population-specific GABAA receptor α1 subunit knockout will advance our understanding of the role of GABAergic synaptic transmission in tremor.
In our extensive literature search, we found that animal models of tremor could be divided into two broad categories: chemical- or lesion-induced (Table 2), or based on genetic mutations (Table 3). However, tremor is usually not the primary interest of these published animal models, and tremor frequency and amplitudes are less defined than in the above-mentioned animal models. In addition, for those with objective tremor measurement, confirmatory studies are needed to better delineate these tremor phenotypes. Moreover, ataxia and tremor are two symptoms related to cerebellar dysfunction. Ataxia is associated with motion irregularity, whereas tremor is movement with defined frequency and rhythm. Therefore, detailed measurement of frequency and variability of motions in animal models should enhance understanding of the brain circuitry for ataxia and tremor.
|Chemical/Lesion||Tremor Type and Frequency (Hz)||Tremor Measurement||Reference|
|Mouse||Harmaline-induced||10–16 Hz body tremor||Force plate-based measurement||19|
|6-OHDA-induced||4–5 Hz body tremor||Electromyography or force plate-based measurement||44|
|Galantamine-induced||Oral tremor (3–7.5 Hz frequency range, with a peak frequency of approximately 6 Hz)||Observation||69|
|Oxotremorine-induced and arecoline-induced||Tremor||Multiple electrical physiological signals real-time analyzer||70|
|Rat||Harmaline-induced||8–12 Hz body tremor||Force plate-based measurement||19|
|Chlordecone-induced||Tremor||Force plate setting||73|
|Ethanol withdrawal physostigmine-induced, arecoline-induced||Tremor(6–7 Hz)tremor (11–13 Hz) tremor (peak of 13 Hz)||Objective measure, not detailed in method||74|
|Monkey||MPTP-induced||5–7 Hz limb tremor||Accelerometer||43|
|Electrical coagulation of the brainstem area including the substantia nigra and the red nucleus||Resting tremor (stable frequency of 4.46 ± 0.59 Hz)||An accelerometer connected to a computer system||79|
|Repeated electrode penetration of the dentate and interpositus nuclei||Change the physiological tremor frequency from 11–13 Hz to 5–7 Hz||EMG||80|
|Partial cerebellectomy (including unilateral DCN)||Tremor||EMG||81|
|Gene/Lesion||Tremor Type (Hz)||Tremor Measure||Ataxia/Others||Cerebellar Pathology/Physiology||Reference|
|Mouse||Car8 mutation||Tremor (4–14 Hz)||Tremor monitor (San Diego instruments)||Ataxia||Microzonal organization defects, abnormal Purkinje cell firing||53|
|crv4 mutation||Intention tremor||Observation||Ataxia||83|
|D801N mutation||Tremor||Observation||Abnormal motor coordination||85|
|GABAA α1 subunit knockout||Tremor (15–19 Hz)||Tremor measured by suspending the tail and attached to the stereo speaker||Absent spontaneous GABAergic inhibitory postsynaptic potentials||66|
|NPC1 mutation||Tremor||Observation||Motor impairment, hyperactivity, impaired learning and memory||86|
|SCN8A mutation||Tremor||Observation||Ataxia and dystonia||Impaired repetitive firing of Purkinje cells in cerebellar slices||87|
|SOD1 mutation||Tremor||Observation||Loss of extension reflex in hind-limbs, decreased grip strength and paralysis||88|
|SULT4A1 mutation||Tremor||Observation||Ataxia and absence seizures||89|
|Vglut2 deletion in the climbing fiber synapses||Tremor (4–14 Hz)||Tremor monitor (San Diego instruments)||Dystonia||Abnormal Purkinje cell simple spike firing (Silencing climbing fiber synaptic transmission)||90|
|Wdr81 mutation||Tremor||Observation||Abnormal gait||Purkinje cell degeneration||91|
|β-III spectrin knockout||Tremor||Observation||Motor incoordination and a wide hindlimb gait||Purkinje cell loss and cerebellar atrophy||92|
|Fig4 knockout||Intention tremor||Observation||hypomyelination of the cerebellum and spongiform degeneration in the deep cerebellar nuclei||93|
|Pura knockout||Action tremor||Observation||Waddling gait||Reduced number of Purkinje cells and granule cells||94|
|Sticky mouse (Aars mutation)||Tremor||Observation||Ataxia||Purkinje cell degeneration||95|
|Scrambler mouse||Body tremor||Observation||Abnormal gait||96|
|Toppler mouse||Action tremor||Observation||Ataxia||Purkinje cell loss||97|
|Wobbler mouse||Head tremor||Observation||Unsteady gait and muscle atrophy||98|
|Weaver mouse||Tremor||Observation||Ataxia and hypertonia||99|
|Rat||VF mutation||Generalized tremor (especially the caudal body) that peaks between 4–8 weeks and gradually subsides||Observation||Abnormal myelin-associated vacuoles in the white matter of cerebellum||100|
|Shaker mutation||Tremor (4–5 Hz)||Force plate-based measurement||Ataxia||Purkinje cell degeneration||60|
|TRM/Kyo mutation||Whole body tremor, responsive to propranolol||Observation||102|
|Hamster||bt mutation||Tremor||Observation||Defective myelination in the central nervous system||101|
In chemically induced animal models of tremor69–81 (Table 2), we found that agents working on the cholinergic axis are able to induce tremor. For example, agents that promote the cholinergic nervous system, such as oxotremorine,70 arecoline,70 nicotine,75 pilocarpine,72 and physostigmine,74 can produce tremor in rodents. Interestingly, promoting muscarinic (oxotremorine), nicotinic (arecoline, pilocarpine, and nicotine), or both (physostigmine) types of cholinergic receptor systems can produce tremor, but whether the tremor characteristics differ in these animal models requires further investigation. One of the clinical implications is that rest tremor in PD can be treated with anticholinergics;82 therefore, rest tremor may be associated with a hypercholinergic state. Further investigation is needed.
In lesion-induced animal models of tremor, we found that cerebellar lesions could produce tremor81 and/or change the frequency of physiological tremor80 in monkeys, highlighting the contribution of the cerebellum to tremor (Table 2).
Finally, there is a list of animal models of tremor with different genetic mutations83–103 (Table 3). Most of the tremor measurements in these animal models are based on observation only and require objective assessment to delineate rest and action tremor, which are the defining features for human tremor disorders. Many of these genetic tremor animal models have a dysfunctional cerebellar circuit (Table 3). The genetic models provide an invaluable resource for stable tremor phenotypes. Additionally, tremor in some of the models is regulated developmentally and throughout adulthood, which can be further studied to understand the role of aging in the underlying neuropathology and physiology.
Animal models of tremor allow researchers to perform detailed physiological studies and brain circuitry dissections using optogenetic tools or electric stimulations. Therefore, animal models can be considered as tools to understand tremor disorders. In the present paper we posit a question: “How do animal models of tremor help us to move towards a better understanding of the current controversies in the tremor field?” To answer this question, we will discuss two major controversies in the tremor field: 1) the relationship between tremor and dystonia, 2) the relationship between ET and PD.
Many ET patients have co-existing dystonic features.4 It remains unclear whether dystonia and tremor are generated from the same or different sources in ET patients with dystonic features. Therefore, we reviewed the literature in animal models, and aimed to find a similarity between tremor and dystonia. Interestingly, both tremor and dystonia could originate from the dysfunctional cerebellum. From a harmaline-induced tremor model, PC rhythmic firing could drive real-time rhythmic motor activities (i.e., tremor).15 In mouse models with viral-mediated DYT1 or DYT12 knockdown in the cerebellum, dystonia may be induced, with a corresponding increased burst firing of PCs.104–106 These studies suggest that real-time abnormalities of PC firing might lead to involuntary movements, which has also been demonstrated by artificially driving PC activities using optogenetics.107 Therefore, abnormal PC firing may be a common neurophysiological underpinning for tremor and a subset of dystonia. Abnormal PC firing could be at times rhythmic and at times high-frequency, burst firing depending on the different stages of the disease process, and these abnormal PC firing patterns may be temporally and spatially segregated within the cerebellar cortex. This can lead to overlapping tremor and dystonia symptoms in different body regions and/or hand positions. Within this framework, the dystonic feature in a subset of ET patients might originate in the cerebellar region. Future studies of different animal models of tremor and dystonia should help to settle this controversy.
The overlapping of symptoms between ET and PD remains controversial. According to epidemiological studies, ET patients have a fivefold increased risk for PD, and these PD patients are often the tremor-predominant type.108,109 Severe ET patients will have rest tremor,108 whereas PD patients often have postural and/or action tremor.110 It is possible that overlap between ET and PD occurs at the brain circuitry level. As mentioned above, the structural changes in the ET cerebellum may generate oscillatory neuronal activities to drive tremor. In PD, dopamine deficiency may cause infrequent tremor, but the structural changes in the cerebellum can amplify this tremor. This dopamine deficiency associated with rest tremor might be at the level of the globes pallid us internal or the ventrolateral thalamus based on human fMRI studies.7,111 A recent study found abnormal CF–PC synaptic connections in the cerebellum of both ET and PD patients,35 possibly demonstrating common brain circuitry abnormalities in these two disorders (Figure 3). This concept is further supported by evidence of the ability of harmaline to intensify rest tremor in monkeys.28 Future studies in animal models should aim to simulate structural changes in the cerebellar circuits and the dopamine system in ET and PD, respectively, such studies should help decode this pathomechanism.
The use of animal models in tremor research is an emerging field. As we begin to comprehensively understand tremor disorders based on genetic, neuroimaging, and neuropathological studies in humans, modeling these genetic and pathological alterations in animal models will greatly advance our understanding of how tremor is generated. Established animal models are likely to provide an important platform to screen therapies for tremor disorders.
1 Funding: Dr. Pan is supported by the Ministry of Science and Technology in Taiwan: MOST 104-2314-B-002-076-MY3 and 107-2321-B-002-020 (principal investigator). Dr. Kuo has received funding from the National Institutes of Health: NINDS #K08 NS083738 (principal investigator) and #R01 NS104423 (principle investigator), and the Louis V. Gerstner Jr. Scholar Award, Parkinson’s Foundation, and International Essential Tremor Foundation.
2 Financial Disclosures: None.
3 Conflicts of Interest: The authors report no conflict of interest.
4 Ethics Statement: This study was reviewed by the authors' institutional ethics committee and was considered exempted from further review.
Thenganatt, MA and Louis, ED (2012). Distinguishing essential tremor from Parkinson’s disease: bedside tests and laboratory evaluations. Exp Rev Neurother 12: 687–696, DOI: https://doi.org/10.1586/ern.12.49
Bhatia, KP, Bain, P, Bajaj, N, Elble, RJ, Hallett, M and Louis, ED (2018). Consensus statement on the classification of tremors. from the task force on tremor of the International Parkinson and Movement Disorder Society. Mov Disord 33: 75–87, DOI: https://doi.org/10.1002/mds.27121 [PubMed]
Schnitzler, A, Münks, C, Butz, M, Timmermann, L and Gross, J (2009). Synchronized brain network associated with essential tremor as revealed by magnetoencephalography. Mov Disord 24: 1629–1635, DOI: https://doi.org/10.1002/mds.22633 [PubMed]
Helmich, RC, Janssen, MJ, Oyen, WJ, Bloem, BR and Toni, I (2011). Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol 69: 269–281, DOI: https://doi.org/10.1002/ana.22361 [PubMed]
Louis, EDE, Faust, PLP, Vonsattel, J-PGJ, Honig, LSL, Rajput, AA and Robinson, CAC (2007). Neuropathological changes in essential tremor: 33 cases compared with 21 controls. Brain 130: 3297–3307, DOI: https://doi.org/10.1093/brain/awm266 [PubMed]
Lee, D, Gan, SR, Faust, PL, Louis, ED and Kuo, SH (2018). Climbing fiber-Purkinje cell synaptic pathology across essential tremor subtypes. Parkinsonism Relar Disord 51: 24–29, DOI: https://doi.org/10.1016/j.parkreldis.2018.02.032
Muthuraman, M, Deuschl, G, Anwar, AR, Mideksa, KG, von Helmolt, F and Schneider, SA (2015). Essential and aging-related tremor: differences of central control. Mov Disord 30: 1673–1680, DOI: https://doi.org/10.1002/mds.26410 [PubMed]
Cheng, MM, Tang, G and Kuo, SH (2013). Harmaline-induced tremor in mice: videotape documentation and open questions about the model. Tremor Other Hyperkinet Mov, : 3.DOI: https://doi.org/10.7916/D8H993W3
Llinas, R and Yarom, Y (1981). Electrophysiology of mammalian inferior olivary neurons in vitro. different types of voltage-dependent ionic conductances. J Physiol 315: 549–567, DOI: https://doi.org/10.1113/jphysiol.1981.sp013763 [PubMed]
Llinás, RR (2013). The olivo-cerebellar system: a key to understanding the functional significance of intrinsic oscillatory brain properties. Front Neural Circuits 7: 96.DOI: https://doi.org/10.3389/fncir.2013.00096 [PubMed]
White, JJ, Lin, T, Brown, AM, Arancillo, M, Lackey, EP and Stay, TL (2016). An optimized surgical approach for obtaining stable extracellular single-unit recordings from the cerebellum of head-fixed behaving mice. J Neurosci Methods 262: 21–31, DOI: https://doi.org/10.1016/j.jneumeth.2016.01.010 [PubMed]
Martin, FC, Thu Le, A and Handforth, A (2005). Harmaline-induced tremor as a potential preclinical screening method for essential tremor medications. Mov Disord 20: 298–305, DOI: https://doi.org/10.1002/mds.20331 [PubMed]
Louis, ED, Zheng, W, Jurewicz, EC, Watner, D, Chen, J and Factor-Litvak, P (2002). Elevation of blood beta-carboline alkaloids in essential tremor. Neurology 59: 1940–1944, DOI: https://doi.org/10.1212/01.WNL.0000038385.60538.19 [PubMed]
Louis, ED, Factor-Litvak, P, Liu, X, Vonsattel, J-PG, Galecki, M and Jiang, W (2013). Elevated brain harmane (1-methyl-9H-pyrido[3,4-b]indole) in essential tremor cases vs. controls. Neurotoxicology 38C: 131–135, DOI: https://doi.org/10.1016/j.neuro.2013.07.002
Martin, FC and Handforth, A (2006). Carbenoxolone and mefloquine suppress tremor in the harmaline mouse model of essential tremor. Mov Disord 21: 1641–1649, DOI: https://doi.org/10.1002/mds.20940 [PubMed]
Handforth, A, Homanics, GE, Covey, DF, Krishnan, K, Lee, JY and Sakimura, K (2010). T-type calcium channel antagonists suppress tremor in two mouse models of essential tremor. Neuropharmacol 59: 380–387, DOI: https://doi.org/10.1016/j.neuropharm.2010.05.012
Lang, EJ, Sugihara, I and Llinas, R (1996). GABAergic modulation of complex spike activity by the cerebellar nucleoolivary pathway in rat. J Neurophysiol 76: 255–275, DOI: https://doi.org/10.1152/jn.19126.96.36.199 [PubMed]
Lang, EJ (2001). Organization of olivocerebellar activity in the absence of excitatory glutamatergic input. J Neurosci 21: 1663–1675, DOI: https://doi.org/10.1523/JNEUROSCI.21-05-01663.2001 [PubMed]
Louis, ED, Babij, R, Cortes, E, Vonsattel, JPG and Faust, PL (2013). The inferior olivary nucleus: a postmortem study of essential tremor cases versus controls. Mov Disord 28: 779–786, DOI: https://doi.org/10.1002/mds.25400 [PubMed]
Long, MA, Deans, MR, Paul, DL and Connors, BW (2002). Rhythmicity without synchrony in the electrically uncoupled inferior olive. J Neurosci 22: 10898–10905, DOI: https://doi.org/10.1523/JNEUROSCI.22-24-10898.2002 [PubMed]
Battista, AF, Nakatani, S, Goldstein, M and Anagnoste, B (1970). Effect of harmaline in monkeys with central nervous system lesions. Exp Neurol 28: 513–524, DOI: https://doi.org/10.1016/0014-4886(70)90189-5 [PubMed]
Lee, J, Kim, I, Lee, J, Knight, E, Cheng, L and Kang, SI (2018). Development of harmaline-induced tremor in a swine model. Tremor Other Hyperkinet Mov 8DOI: https://doi.org/10.7916/D8J68TV7
Miwa, H, Kubo, T, Suzuki, A, Kihira, T and Kondo, T (2006). A species-specific difference in the effects of harmaline on the rodent olivocerebellar system. Brain Res 1068: 94–101, DOI: https://doi.org/10.1016/j.brainres.2005.11.036 [PubMed]
O’Hearn, E and Molliver, ME (1993). Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Neuroscience 55: 303–310, DOI: https://doi.org/10.1016/0306-4522(93)90500-F [PubMed]
Choe, M, Cortes, E, Vonsattel, JP, Kuo, SH, Faust, PL and Louis, ED (2016). Purkinje cell loss in essential tremor: Random sampling quantification and nearest neighbor analysis. Mov Disord 31: 393–401, DOI: https://doi.org/10.1002/mds.26490 [PubMed]
Paterson, NE, Malekiani, SA, Foreman, MM, Olivier, B and Hanania, T (2009). Pharmacological characterization of harmaline-induced tremor activity in mice. Eur J Pharmacol 616: 73–80, DOI: https://doi.org/10.1016/j.ejphar.2009.05.031 [PubMed]
Kuo, SH, Lin, CY, Wang, J, Liou, JY, Pan, MK and Louis, RJ (2016). Deep brain stimulation and climbing fiber synaptic pathology in essential tremor. Ann Neurol 80: 461–465, DOI: https://doi.org/10.1002/ana.24728 [PubMed]
Kuo, SH, Lin, CY, Wang, J, Sims, PA, Pan, MK and Liou, JY (2017). Climbing fiber-Purkinje cell synaptic pathology in tremor and cerebellar degenerative diseases. Acta Neuropathol 133: 121–138, DOI: https://doi.org/10.1007/s00401-016-1626-1 [PubMed]
Lin, C-Y, Louis, ED, Faust, PL, Koeppen, AH, Vonsattel, J-PG and Kuo, S-H (2014). Abnormal climbing fibre-Purkinje cell synaptic connections in the essential tremor cerebellum. Brain 137: 3149–3159, DOI: https://doi.org/10.1093/brain/awu281 [PubMed]
Louis, RJ, Lin, C-Y, Faust, PL, Koeppen, AH and Kuo, S-H (2015). Climbing fiber synaptic changes correlate with clinical features in essential tremor. 84: 2284.DOI: https://doi.org/10.1212/WNL.0000000000001636
Yoshida, T, Katoh, A, Ohtsuki, G, Mishina, M and Hirano, T (2004). Oscillating Purkinje neuron activity causing involuntary eye movement in a mutant mouse deficient in the glutamate receptor delta2 subunit. J Neurosci 24: 2440–2448, DOI: https://doi.org/10.1523/JNEUROSCI.0783-03.2004 [PubMed]
Babij, R, Lee, M, Cortes, E, Vonsattel, JPG, Faust, PL and Louis, ED (2013). Purkinje cell axonal anatomy: quantifying morphometric changes in essential tremor versus control brains. Brain 136: 3051–3061, DOI: https://doi.org/10.1093/brain/awt238 [PubMed]
Bergman, H, Raz, A, Feingold, A, Nini, A, Nelken, I and Hansel, D (1998). Physiology of MPTP tremor. Mov Disord 13(Suppl. 3): 29–34, DOI: https://doi.org/10.1002/mds.870131305
Bekar, L, Libionka, W, Tian, GF, Xu, Q, Torres, A and Wang, X (2008). Adenosine is crucial for deep brain stimulation-mediated attenuation of tremor. Nat Med 14: 75–80, DOI: https://doi.org/10.1038/nm1693 [PubMed]
Deutch, AY, Elsworth, JD, Goldstein, M, Fuxe, K, Redmond, DE Jr and Sladek, JR (1986). Preferential vulnerability of A8 dopamine neurons in the primate to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neurosci Lett 68: 51–56, DOI: https://doi.org/10.1016/0304-3940(86)90228-4 [PubMed]
German, DC, Dubach, M, Askari, S, Speciale, SG and Bowden, DM (1988). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian syndrome in Macaca fascicularis: which midbrain dopaminergic neurons are lost?. Neuroscience 24: 161–174, DOI: https://doi.org/10.1016/0306-4522(88)90320-X [PubMed]
Oiwa, Y, Eberling, JL, Nagy, D, Pivirotto, P, Emborg, ME and Bankiewicz, KS (2003). Overlesioned hemiparkinsonian non-human primate model: correlation between clinical, neurochemical and histochemical changes. Front Biosci 8: a155–166, DOI: https://doi.org/10.2741/1104 [PubMed]
Rivlin-Etzion, M, Elias, S, Heimer, G and Bergman, H (2010). Computational physiology of the basal ganglia in Parkinson's disease. Prog Brain Res 183: 259–273, DOI: https://doi.org/10.1016/S0079-6123(10)83013-4 [PubMed]
Dirkx, MF, den Ouden, H, Aarts, E, Timmer, M, Bloem, BR and Toni, I (2016). The cerebral network of Parkinson's tremor: an effective connectivity fMRI study. J Neurosci 36: 5362–5372, DOI: https://doi.org/10.1523/JNEUROSCI.3634-15.2016 [PubMed]
Helmich, RC, Hallett, M, Deuschl, G, Toni, I and Bloem, BR (2012). Cerebral causes and consequences of parkinsonian resting tremor: a tale of two circuits?. Brain 135: 3206–3226, DOI: https://doi.org/10.1093/brain/aws023 [PubMed]
Schuurman, PR, Bosch, DA, Bossuyt, PM, Bonsel, GJ, van Someren, EJ and de Bie, RM (2000). A comparison of continuous thalamic stimulation and thalamotomy for suppression of severe tremor. New Engl J Med 342: 461–468, DOI: https://doi.org/10.1056/NEJM200002173420703 [PubMed]
Meyer, PT, Frings, L, Rucker, G and Hellwig, S (2017). (18)F-FDG PET in Parkinsonism: differential diagnosis and evaluation of cognitive impairment. J Nuclear Med 58: 1888–1898, DOI: https://doi.org/10.2967/jnumed.116.186403
White, JJ, Arancillo, M, King, A, Lin, T, Miterko, LN and Gebre, SA (2016). Pathogenesis of severe ataxia and tremor without the typical signs of neurodegeneration. Neurobiol Disease 86: 86–98, DOI: https://doi.org/10.1016/j.nbd.2015.11.008
Beckinghausen, J and Sillitoe, RV (2018). Insights into cerebellar development and connectivity. Neurosci Lett, DOI: https://doi.org/10.1016/j.neulet.2018.05.013
Apps, R, Hawkes, R, Aoki, S, Bengtsson, F, Brown, AM and Chen, G (2018). Cerebellar modules and their role as operational cerebellar processing units. Cerebellum 17: 654–682, DOI: https://doi.org/10.1007/s12311-018-0959-9
Turkmen, S, Guo, G, Garshasbi, M, Hoffmann, K, Alshalah, AJ and Mischung, C (2009). CA8 mutations cause a novel syndrome characterized by ataxia and mild mental retardation with predisposition to quadrupedal gait. PLoS Genet 5: e1000487.DOI: https://doi.org/10.1371/journal.pgen.1000487 [PubMed]
Kaya, N, Aldhalaan, H, Al-Younes, B, Colak, D, Shuaib, T and Al-Mohaileb, F (2011). Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII. Am J Med Genet B, Neuropsychiatric Genet 156b: 826–834, DOI: https://doi.org/10.1002/ajmg.b.31227
Clark, BR, LaRegina, M and Tolbert, DL (2000). X-linked transmission of the shaker mutation in rats with hereditary Purkinje cell degeneration and ataxia. Brain Res 858: 264–273, DOI: https://doi.org/10.1016/S0006-8993(99)02415-4 [PubMed]
Gan, SR, Wang, J, Figueroa, KP, Pulst, SM, Tomishon, D and Lee, D (2017). Postural tremor and ataxia progression in spinocerebellar ataxias. Tremor Other Hyperkinet Mov 7DOI: https://doi.org/10.7916/D8GM8KRH
Schaefer, SM, Vives Rodriguez, A and Louis, ED (2018). Brain circuits and neurochemical systems in essential tremor: insights into current and future pharmacotherapeutic approaches. Exp Rev Neurother 18: 101–110, DOI: https://doi.org/10.1080/14737175.2018.1413353
Zesiewicz, TA and Kuo, SH (2015). Essential tremor. BMJ Clin Evid, DOI: https://doi.org/10.1212/WNL.0000000000004372
Paris-Robidas, S, Brochu, E, Sintes, M, Emond, V, Bousquet, M and Vandal, M (2012). Defective dentate nucleus GABA receptors in essential tremor. Brain 135: 105–116, DOI: https://doi.org/10.1093/brain/awr301 [PubMed]
Kralic, JE, Criswell, HE, Osterman, JL, O’Buckley, TK, Wilkie, ME and Matthews, DB (2005). Genetic essential tremor in gamma-aminobutyric acidA receptor alpha1 subunit knockout mice. The J Clin Invest 115: 774–779, DOI: https://doi.org/10.1172/JCI200523625 [PubMed]
Louis, ED, Hernandez, N, Dyke, JP, Ma, RE and Dydak, U (2018). In vivo dentate nucleus gamma-aminobutyric acid concentration in essential tremor vs. controls. Cerebellum 17: 165–172, DOI: https://doi.org/10.1007/s12311-017-0891-4 [PubMed]
Boecker, H, Weindl, A, Brooks, DJ, Ceballos-Baumann, AO, Liedtke, C and Miederer, M (2010). GABAergic dysfunction in essential tremor: an 11C-flumazenil PET study. J Nuclear Med 51: 1030–1035, DOI: https://doi.org/10.2967/jnumed.109.074120
Podurgiel, SJ, Spencer, T, Kovner, R, Baqi, Y, Muller, CE and Correa, M (2016). Induction of oral tremor in mice by the acetylcholinesterase inhibitor galantamine: reversal with adenosine A2A antagonism. Pharmacol Biochem Behav 140: 62–67, DOI: https://doi.org/10.1016/j.pbb.2015.10.008 [PubMed]
Nannan, G, Runmei, Y, Fusheng, L, Shoulan, Z and Guangqing, L (2007). Effects of AIT-082, a purine derivative, on tremor induced by arecoline or oxotremorine in mice. Pharmacol 80: 21–26, DOI: https://doi.org/10.1159/000102601
Salamone, JD, Collins-Praino, LE, Pardo, M, Podurgiel, SJ, Baqi, Y and Muller, CE (2013). Conditional neural knockout of the adenosine A(2A) receptor and pharmacological A(2A) antagonism reduce pilocarpine-induced tremulous jaw movements: studies with a mouse model of parkinsonian tremor. Eur Neuropsychopharmacol 23: 972–977, DOI: https://doi.org/10.1016/j.euroneuro.2012.08.004 [PubMed]
Chen, PH, Tilson, HA, Marbury, GD, Karoum, F and Hong, JS (1985). Effect of chlordecone (Kepone) on the rat brain concentration of 3-methoxy-4-hydroxyphenylglycol: evidence for a possible involvement of the norepinephrine system in chlordecone-induced tremor. Toxicol Appl Pharmacol 77: 158–164, DOI: https://doi.org/10.1016/0041-008X(85)90276-5 [PubMed]
Gothoni, P (1985). Ethanol withdrawal tremor does not interact with physostigmine-induced tremor in rat. Pharmacol Biochem Behav 23: 339–344, DOI: https://doi.org/10.1016/0091-3057(85)90003-6 [PubMed]
Mansner, R and Mattila, MJ (1975). Nicotine induced tremor and antidiuresis and brain nicotine levels in the rat. Med Biol 53: 169–176. [PubMed]
Growdon, JH (1977). Postural changes, tremor, and myoclonus in the rat immediately following injections of p-chloromaphetamine. Neurology 27: 1074–1077, DOI: https://doi.org/10.1212/WNL.27.11.1074 [PubMed]
Hudson, PM, Chen, PH, Tilson, HA and Hong, JS (1985). Effects of p,p'-DDT on the rat brain concentrations of biogenic amine and amino acid neurotransmitters and their association with p,p'-DDT-induced tremor and hyperthermia. J Neurochem 45: 1349–1355, DOI: https://doi.org/10.1111/j.1471-4159.1985.tb07199.x [PubMed]
Vanover, KE, Betz, AJ, Weber, SM, Bibbiani, F, Kielaite, A and Weiner, DM (2008). A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model. Pharmacol Biochem Behav 90: 540–544, DOI: https://doi.org/10.1016/j.pbb.2008.04.010 [PubMed]
Gao, DM, Benazzouz, A, Piallat, B, Bressand, K, Ilinsky, IA and Kultas-Ilinsky, K (1999). High-frequency stimulation of the subthalamic nucleus suppresses experimental resting tremor in the monkey. Neuroscience 88: 201–212, DOI: https://doi.org/10.1016/S0306-4522(98)00235-8 [PubMed]
Elble, RJ, Schieber, MH and Thach, WT Jr (1984). Activity of muscle spindles, motor cortex and cerebellar nuclei during action tremor. Brain Res 323: 330–334, DOI: https://doi.org/10.1016/0006-8993(84)90308-1 [PubMed]
Koller, WC (1986). Pharmacologic treatment of parkinsonian tremor. Arch Neurol 43: 126–127, DOI: https://doi.org/10.1001/archneur.1986.00520020020009 [PubMed]
Conti, V, Aghaie, A, Cilli, M, Martin, N, Caridi, G and Musante, L (2006). crv4, a mouse model for human ataxia associated with kyphoscoliosis caused by an mRNA splicing mutation of the metabotropic glutamate receptor 1 (Grm1). Int J Mol Mede 18: 593–600, DOI: https://doi.org/10.3892/ijmm.18.4.593
Zhao, L, Hadziahmetovic, M, Wang, C, Xu, X, Song, Y and Jinnah, HA (2015). Cp/Heph mutant mice have iron-induced neurodegeneration diminished by deferiprone. J Neurochem 135: 958–974, DOI: https://doi.org/10.1111/jnc.13292 [PubMed]
Hunanyan, AS, Fainberg, NA, Linabarger, M, Arehart, E, Leonard, AS and Adil, SM (2015). Knock-in mouse model of alternating hemiplegia of childhood: behavioral and electrophysiologic characterization. Epilepsia 56: 82–93, DOI: https://doi.org/10.1111/epi.12878 [PubMed]
Gomez-Grau, M, Albaiges, J, Casas, J, Auladell, C, Dierssen, M and Vilageliu, L (2017). New murine Niemann-Pick type C models bearing a pseudoexon-generating mutation recapitulate the main neurobehavioural and molecular features of the disease. Sci Rep 7: 41931.DOI: https://doi.org/10.1038/srep41931 [PubMed]
Jones, JM, Dionne, L, Dell’Orco, J, Parent, R, Krueger, JN and Cheng, X (2016). Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder. Neurobiol Dis 89: 36–45, DOI: https://doi.org/10.1016/j.nbd.2016.01.018 [PubMed]
Killoy, KM, Harlan, BA, Pehar, M, Helke, KL, Johnson, JA and Vargas, MR (2018). Decreased glutathione levels cause overt motor neuron degeneration in hSOD1(WT) over-expressing mice. Exp Neurol 302: 129–135, DOI: https://doi.org/10.1016/j.expneurol.2018.01.004 [PubMed]
Garcia, PL, Hossain, MI, Andrabi, SA and Falany, CN (2018). Generation and characterization of SULT4A1 mutant mouse models. Drug Metab Dispos 46: 41–45, DOI: https://doi.org/10.1124/dmd.117.077560 [PubMed]
White, JJ and Sillitoe, RV (2017). Genetic silencing of olivocerebellar synapses causes dystonia-like behaviour in mice. Nat Comm 8: 14912.DOI: https://doi.org/10.1038/ncomms14912
Traka, M, Millen, KJ, Collins, D, Elbaz, B, Kidd, GJ and Gomez, CM (2013). WDR81 is necessary for Purkinje and photoreceptor cell survival. J Neurosci 33: 6834–6844, DOI: https://doi.org/10.1523/JNEUROSCI.2394-12.2013 [PubMed]
Perkins, EM, Clarkson, YL, Sabatier, N, Longhurst, DM, Millward, CP and Jack, J (2010). Loss of beta-III spectrin leads to Purkinje cell dysfunction recapitulating the behavior and neuropathology of spinocerebellar ataxia type 5 in humans. J Neurosci 30: 4857–4867, DOI: https://doi.org/10.1523/JNEUROSCI.6065-09.2010 [PubMed]
Mironova, YA, Lin, JP, Kalinski, A, Huffman, L, Lenk, GM and Havton, LA (2018). Protective role of the lipid phosphatase Fig4 in the adult nervous system. Hum Mol Genet 27: 2443–2453, DOI: https://doi.org/10.1093/hmg/ddy145 [PubMed]
Khalili, K, Del Valle, L, Muralidharan, V, Gault, WJ, Darbinian, N and Otte, J (2003). Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse. Mol Cell Biol 23: 6857–6875, DOI: https://doi.org/10.1128/MCB.23.19.6857-6875.2003 [PubMed]
Jacquelin, C, Strazielle, C and Lalonde, R (2012). Neurologic function during developmental and adult stages in Dab1(scm) (scrambler) mutant mice. Behav Brain Res 226: 265–273, DOI: https://doi.org/10.1016/j.bbr.2011.09.020 [PubMed]
Duchala, CS, Shick, HE, Garcia, J, Deweese, DM, Sun, X and Stewart, VJ (2004). The toppler mouse: a novel mutant exhibiting loss of Purkinje cells. J Comp Neurol 476: 113–129, DOI: https://doi.org/10.1002/cne.20206 [PubMed]
Grusser-Cornehls, U, Grusser, C and Baurle, J (1999). Vermectomy enhances parvalbumin expression and improves motor performance in weaver mutant mice: an animal model for cerebellar ataxia. Neuroscience 91: 315–326, DOI: https://doi.org/10.1016/S0306-4522(98)00618-6 [PubMed]
Tanaka, M, Soma, K, Izawa, T, Yamate, J, Franklin, RJ and Kuramoto, T (2012). Abnormal myelinogenesis in the central nervous system of the VF mutant rat with recoverable tremor. Brain Res 1488: 104–112, DOI: https://doi.org/10.1016/j.brainres.2012.09.037 [PubMed]
Kuramoto, T, Nomoto, T, Fujiwara, A, Mizutani, M, Sugimura, T and Ushijima, T (2002). Insertional mutation of the Attractin gene in the black tremor hamster. Mamm Genome 13: 36–40, DOI: https://doi.org/10.1007/s00335-001-2116-9 [PubMed]
Nishitani, A, Tanaka, M, Shimizu, S, Kunisawa, N, Yokoe, M and Yoshida, Y (2016). Involvement of aspartoacylase in tremor expression in rats. Exp Anim 65: 293–301, DOI: https://doi.org/10.1538/expanim.16-0007 [PubMed]
Ohno, Y, Shimizu, S, Tatara, A, Imaoku, T, Ishii, T and Sasa, M (2015). Hcn1 is a tremorgenic genetic component in a rat model of essential tremor. PloS one 10: e0123529.DOI: https://doi.org/10.1371/journal.pone.0123529 [PubMed]
Fremont, R, Calderon, DP, Maleki, S and Khodakhah, K (2014). Abnormal high-frequency burst firing of cerebellar neurons in rapid-onset dystonia-parkinsonism. J Neurosci 34: 11723–11732, DOI: https://doi.org/10.1523/JNEUROSCI.1409-14.2014 [PubMed]
Fremont, R, Tewari, A and Khodakhah, K (2015). Aberrant Purkinje cell activity is the cause of dystonia in a shRNA-based mouse model of Rapid Onset Dystonia-Parkinsonism. Neurobiol Dis 82: 200–212, DOI: https://doi.org/10.1016/j.nbd.2015.06.004 [PubMed]
Fremont, R, Tewari, A, Angueyra, C and Khodakhah, K (2017). A role for cerebellum in the hereditary dystonia DYT1. eLife, : 6.DOI: https://doi.org/10.7554/eLife.22775.001
Lee, KH, Mathews, PJ, Reeves, AM, Choe, KY, Jami, SA and Serrano, RE (2015). Circuit mechanisms underlying motor memory formation in the cerebellum. Neuron 86: 529–540, DOI: https://doi.org/10.1016/j.neuron.2015.03.010 [PubMed]
Thenganatt, MA and Jankovic, J (2016). The relationship between essential tremor and Parkinson's disease. Parkinsonism Relat Disord 22(Suppl. 1): S162–165, DOI: https://doi.org/10.1016/j.parkreldis.2015.09.032 [PubMed]
Shahed, J and Jankovic, J (2007). Exploring the relationship between essential tremor and Parkinson’s disease. Parkinsonism Relat Disord 13: 67–76, DOI: https://doi.org/10.1016/j.parkreldis.2006.05.033 [PubMed]
Dirkx, MF, Zach, H, Bloem, BR, Hallett, M and Helmich, RC (2018). The nature of postural tremor in Parkinson disease. Neurology 90(13): e1095–e1103, DOI: https://doi.org/10.1212/WNL.0000000000005215 [PubMed]
Dirkx, MF, den Ouden, HE, Aarts, E, Timmer, MH, Bloem, BR and Toni, I (2017). Dopamine controls Parkinson's tremor by inhibiting the cerebellar thalamus. Brain 140: 721–734, DOI: https://doi.org/10.1212/WNL.0000000000005215 [PubMed]