Harmaline Tremor: Underlying Mechanisms in a Potential Animal Model of Essential Tremor

Handforth, Adrian

doi:10.7916/d8td9w2p

Cited by 47 publications

(8 citation statements)

References 150 publications

(161 reference statements)

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“…Intraperitoneal administration of harmaline into mice (Fig. 1a) 21,22 induces rhythmic burst-firing activity in the olivary nuclei that is transmitted to the spinal cord and eventually results in muscle tremor 23 . We tested the effect of activating spinal CB receptors in this model by intrathecal lumbar administration of the highly potent CB agonist WIN55,212-2.…”

Section: Spinal Cannabinoids Receptors Reduce Tremor In Vivomentioning

confidence: 99%

Spinal astroglial cannabinoid receptors control pathological tremor

et al. 2021

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Cannabinoids reduce tremor associated with motor disorders induced by injuries and neurodegenerative disease. Here we show that this effect is mediated by cannabinoid receptors on astrocytes in the ventral horn of the spinal cord, where alternating limb movements are initiated. We first demonstrate that tremor is reduced in a mouse model of essential tremor after intrathecal injection of the cannabinoid analog WIN55,212-2. We investigate the underlying mechanism using electrophysiological recordings in spinal cord slices and show that endocannabinoids released from depolarized interneurons activate astrocytic cannabinoid receptors, causing an increase in intracellular Ca 2+ , subsequent release of purines, and inhibition of excitatory neurotransmission. Finally, we show that the anti-tremor action of WIN55,212-2 in the spinal cords of mice is suppressed after knocking out CB 1 receptors in astrocytes. Our data suggest that cannabinoids reduce tremor via their action on spinal astrocytes.Everyone experiences the involuntary, rhythmic, oscillatory movement of body parts that is known as tremor 1 . Physiological tremor is not a burden due to its modest amplitude. In contrast, pathological forms of tremor can be extremely disabling for patients 2 , and can Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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Section: Spinal Cannabinoids Receptors Reduce Tremor In Vivomentioning

confidence: 99%

Spinal astroglial cannabinoid receptors control pathological tremor

et al. 2021

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“…Previous research has qualitatively described harmaline-induced tremor as an action tremor (Placantonakis et al, 2004 ; Handforth, 2012 ), akin to the action tremor phenotype observed with ET (Bhatia et al, 2018 ). Our results support this observation, demonstrating that harmaline tremor significantly increases in amplitude during movement compared to rest.…”

Section: Discussionmentioning

confidence: 90%

“…Although harmaline-induced tremor and ET show similarities in their phenotype and electrophysiological correlates, differences in the aetiology of tremor remain. Harmaline has been well-documented to produce a tremor by increasing the rhythmicity and frequency of olivo-cerebellar inputs (for a review see Handforth, 2012 ). However, there is little evidence for the involvement of hyper-oscillatory olivo-cerebellar activity in ET.…”

Section: Discussionmentioning

confidence: 99%

“…Harmaline-induced tremor is characterised as an action tremor, akin to ET, with the frequency of tremor varying slightly across species (10–16 Hz in mice, 8–12 Hz in rats, 7–12 Hz in monkeys, and 10–16 Hz in pigs; Lamarre et al, 1975 ; Martin et al, 2005 ; Lee J. et al, 2018 ). Harmaline tremor shares similar underlying neural pathways as ET (Handforth, 2012 ). For example, electrical stimulation within the thalamus in harmaline-treated mice and rats significantly reduces the amplitude of harmaline-induced tremor, akin to the effects of deep brain stimulation observed in ET patients (Bekar et al, 2008 ; Lee and Chang, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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Cerebello-Thalamo-Cortical Network Dynamics in the Harmaline Rodent Model of Essential Tremor

Woodward

Apps

Goodfellow

et al. 2022

Front. Syst. Neurosci.

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Essential Tremor (ET) is a common movement disorder, characterised by a posture or movement-related tremor of the upper limbs. Abnormalities within cerebellar circuits are thought to underlie the pathogenesis of ET, resulting in aberrant synchronous oscillatory activity within the thalamo-cortical network leading to tremors. Harmaline produces pathological oscillations within the cerebellum, and a tremor that phenotypically resembles ET. However, the neural network dynamics in cerebellar-thalamo-cortical circuits in harmaline-induced tremor remains unclear, including the way circuit interactions may be influenced by behavioural state. Here, we examined the effect of harmaline on cerebello-thalamo-cortical oscillations during rest and movement. EEG recordings from the sensorimotor cortex and local field potentials (LFP) from thalamic and medial cerebellar nuclei were simultaneously recorded in awake behaving rats, alongside measures of tremor using EMG and accelerometery. Analyses compared neural oscillations before and after systemic administration of harmaline (10 mg/kg, I.P), and coherence across periods when rats were resting vs. moving. During movement, harmaline increased the 9–15 Hz behavioural tremor amplitude and increased thalamic LFP coherence with tremor. Medial cerebellar nuclei and cerebellar vermis LFP coherence with tremor however remained unchanged from rest. These findings suggest harmaline-induced cerebellar oscillations are independent of behavioural state and associated changes in tremor amplitude. By contrast, thalamic oscillations are dependent on behavioural state and related changes in tremor amplitude. This study provides new insights into the role of cerebello-thalamo-cortical network interactions in tremor, whereby neural oscillations in thalamocortical, but not cerebellar circuits can be influenced by movement and/or behavioural tremor amplitude in the harmaline model.

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“…Harmaline-induced tremor can be dampened by ET medications, propranolol, primidone, and alcohol [93]. Harmaline induces tremor by enhancing the automaticity in the inferior olivary neurons via a mixture of proposed pharmacological actions related to NMDA channels [94], T-type calcium channels [95], and possibly gap junctions between inferior olivary neurons for electrical coupling [96]. Gap junctions in the inferior olivary neurons serve as electrical synapses to synchronize their neuronal activity [97,98].…”

Section: β-Carboline Alkaloid Exposures and Related Tremormentioning

confidence: 99%