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according to an investigation published January 15 in Science Translational Medicine. These synaptic pruning deficits result from insufficiency of glutamate receptor delta 2 (GluR[delta]2) protein. The findings indicate molecular, structural, physiological, and behavioral factors that contribute to tremor and might influence future treatment of essential tremor, the authors wrote.
Essential tremor has a complex etiology that includes genetic and environmental factors. Its pathophysiology is poorly understood. First author Ming-Kai Pan, MD, assistant professor of medical research and neurology at National Taiwan University Hospital in Taipei, and colleagues previously observed pruning deficits of CF-PC synapses in the cerebellum of deceased patients with essential tremor. An excess of CF-PC synapses are a prominent feature of essential tremor, but not of other cerebellar degenerative disorders. Researchers have observed this pathology consistently in patients with essential tremor who have diverse clinical features. Dr. Pan and colleagues therefore chose to examine these synaptic changes to clarify the pathophysiology of essential tremor.
Patients had more CF synapses than did controls
The investigators performed a pathological examination of postmortem cerebellar tissue from patients with essential tremor and controls to identify microstructural changes in essential tremor. Next, they applied these changes to mouse models of essential tremor and examined the corresponding structural, electrophysiologic, and behavioral changes. Finally, Dr. Pan and colleagues used cerebellar EEG to validate their findings in patients with essential tremor.
Compared with age-matched controls, patients with essential tremor had more CF synapses in the parallel-fiber synaptic territory on PC dendrites. Patients also had an approximately 75% reduction in mean GluR(delta)2 expression, compared with controls. The amount of GluR(delta)2 was inversely correlated with the percentage of CFs extending to parallel-fiber synaptic territory. The findings suggest that PC synaptic pathology in essential tremor might be related to reduced GluR(delta)2 expression, Dr. Pan and colleagues wrote.
The investigators examined a mouse model that produces 10% of full-length GluR(delta)2 protein. These mice had significant reduction of GluR(delta)2 in the cerebellar cortex and the PC dendrites. In addition, the mice consistently developed CF synapses innervating distal, thin PC dendrites. The investigators observed a 20-Hz tremor in the mice that occurred mainly during action and rarely during rest.
Dr. Pan and colleagues injected a virus containing GluR(delta)2 protein into the mice’s brains to test the protein’s relationship to tremor. Five days after the injection, the mice’s brains were expressing GluR(delta)2 protein reliably. By 4-6 days after injection, the mice’s tremor had been reduced. It returned to baseline levels at 12-14 days after injection. Injecting a control virus did not affect tremor.
Cerebellar oscillatory indexes were correlated with tremor scores
When the researchers examined local field potentials in mouse cerebellum, they found cerebellar oscillations at 20 Hz that were consistent with the observed tremor. “Putting the evidence together, GluR(delta)2 insufficiency causes CF synaptic pruning deficits, and the surplus CF-PC synaptic activity generates excessive cerebellar oscillations, which drive tremor,” Dr. Pan and colleagues reported.
Next, the researchers performed cerebellar EEG in 10 patients with essential tremor and 10 age-matched controls. Patients had cerebellar oscillations at 4-12 Hz, which are the human tremor frequencies. In an expanded cohort of 20 patients with essential tremor and 20 controls, the cerebellar oscillatory indexes were correlated with tremor scores in patients, which showed that the former could be an index of tremor severity. “Currently, diagnosis of essential tremor is based on pure clinical tremor phenomenology and direct tremor measurement, without a physiological marker indicating the underlying brain circuitry abnormalities,” they wrote. “Cerebellar oscillations can be a physiological signature and a therapeutic target for essential tremor.”
The research was funded by grants from the National Institutes of Health, the Parkinson’s Foundation, the International Essential Tremor Foundation, the Ministry of Science and Technology in Taiwan, and the National Taiwan University Hospital. The authors declared that they had no competing interests.
SOURCE: Pan M-K et al. Sci Transl Med. 2020;12:eaay1769. doi: 10.1126/scitranslmed.aay1769.
according to an investigation published January 15 in Science Translational Medicine. These synaptic pruning deficits result from insufficiency of glutamate receptor delta 2 (GluR[delta]2) protein. The findings indicate molecular, structural, physiological, and behavioral factors that contribute to tremor and might influence future treatment of essential tremor, the authors wrote.
Essential tremor has a complex etiology that includes genetic and environmental factors. Its pathophysiology is poorly understood. First author Ming-Kai Pan, MD, assistant professor of medical research and neurology at National Taiwan University Hospital in Taipei, and colleagues previously observed pruning deficits of CF-PC synapses in the cerebellum of deceased patients with essential tremor. An excess of CF-PC synapses are a prominent feature of essential tremor, but not of other cerebellar degenerative disorders. Researchers have observed this pathology consistently in patients with essential tremor who have diverse clinical features. Dr. Pan and colleagues therefore chose to examine these synaptic changes to clarify the pathophysiology of essential tremor.
Patients had more CF synapses than did controls
The investigators performed a pathological examination of postmortem cerebellar tissue from patients with essential tremor and controls to identify microstructural changes in essential tremor. Next, they applied these changes to mouse models of essential tremor and examined the corresponding structural, electrophysiologic, and behavioral changes. Finally, Dr. Pan and colleagues used cerebellar EEG to validate their findings in patients with essential tremor.
Compared with age-matched controls, patients with essential tremor had more CF synapses in the parallel-fiber synaptic territory on PC dendrites. Patients also had an approximately 75% reduction in mean GluR(delta)2 expression, compared with controls. The amount of GluR(delta)2 was inversely correlated with the percentage of CFs extending to parallel-fiber synaptic territory. The findings suggest that PC synaptic pathology in essential tremor might be related to reduced GluR(delta)2 expression, Dr. Pan and colleagues wrote.
The investigators examined a mouse model that produces 10% of full-length GluR(delta)2 protein. These mice had significant reduction of GluR(delta)2 in the cerebellar cortex and the PC dendrites. In addition, the mice consistently developed CF synapses innervating distal, thin PC dendrites. The investigators observed a 20-Hz tremor in the mice that occurred mainly during action and rarely during rest.
Dr. Pan and colleagues injected a virus containing GluR(delta)2 protein into the mice’s brains to test the protein’s relationship to tremor. Five days after the injection, the mice’s brains were expressing GluR(delta)2 protein reliably. By 4-6 days after injection, the mice’s tremor had been reduced. It returned to baseline levels at 12-14 days after injection. Injecting a control virus did not affect tremor.
Cerebellar oscillatory indexes were correlated with tremor scores
When the researchers examined local field potentials in mouse cerebellum, they found cerebellar oscillations at 20 Hz that were consistent with the observed tremor. “Putting the evidence together, GluR(delta)2 insufficiency causes CF synaptic pruning deficits, and the surplus CF-PC synaptic activity generates excessive cerebellar oscillations, which drive tremor,” Dr. Pan and colleagues reported.
Next, the researchers performed cerebellar EEG in 10 patients with essential tremor and 10 age-matched controls. Patients had cerebellar oscillations at 4-12 Hz, which are the human tremor frequencies. In an expanded cohort of 20 patients with essential tremor and 20 controls, the cerebellar oscillatory indexes were correlated with tremor scores in patients, which showed that the former could be an index of tremor severity. “Currently, diagnosis of essential tremor is based on pure clinical tremor phenomenology and direct tremor measurement, without a physiological marker indicating the underlying brain circuitry abnormalities,” they wrote. “Cerebellar oscillations can be a physiological signature and a therapeutic target for essential tremor.”
The research was funded by grants from the National Institutes of Health, the Parkinson’s Foundation, the International Essential Tremor Foundation, the Ministry of Science and Technology in Taiwan, and the National Taiwan University Hospital. The authors declared that they had no competing interests.
SOURCE: Pan M-K et al. Sci Transl Med. 2020;12:eaay1769. doi: 10.1126/scitranslmed.aay1769.
according to an investigation published January 15 in Science Translational Medicine. These synaptic pruning deficits result from insufficiency of glutamate receptor delta 2 (GluR[delta]2) protein. The findings indicate molecular, structural, physiological, and behavioral factors that contribute to tremor and might influence future treatment of essential tremor, the authors wrote.
Essential tremor has a complex etiology that includes genetic and environmental factors. Its pathophysiology is poorly understood. First author Ming-Kai Pan, MD, assistant professor of medical research and neurology at National Taiwan University Hospital in Taipei, and colleagues previously observed pruning deficits of CF-PC synapses in the cerebellum of deceased patients with essential tremor. An excess of CF-PC synapses are a prominent feature of essential tremor, but not of other cerebellar degenerative disorders. Researchers have observed this pathology consistently in patients with essential tremor who have diverse clinical features. Dr. Pan and colleagues therefore chose to examine these synaptic changes to clarify the pathophysiology of essential tremor.
Patients had more CF synapses than did controls
The investigators performed a pathological examination of postmortem cerebellar tissue from patients with essential tremor and controls to identify microstructural changes in essential tremor. Next, they applied these changes to mouse models of essential tremor and examined the corresponding structural, electrophysiologic, and behavioral changes. Finally, Dr. Pan and colleagues used cerebellar EEG to validate their findings in patients with essential tremor.
Compared with age-matched controls, patients with essential tremor had more CF synapses in the parallel-fiber synaptic territory on PC dendrites. Patients also had an approximately 75% reduction in mean GluR(delta)2 expression, compared with controls. The amount of GluR(delta)2 was inversely correlated with the percentage of CFs extending to parallel-fiber synaptic territory. The findings suggest that PC synaptic pathology in essential tremor might be related to reduced GluR(delta)2 expression, Dr. Pan and colleagues wrote.
The investigators examined a mouse model that produces 10% of full-length GluR(delta)2 protein. These mice had significant reduction of GluR(delta)2 in the cerebellar cortex and the PC dendrites. In addition, the mice consistently developed CF synapses innervating distal, thin PC dendrites. The investigators observed a 20-Hz tremor in the mice that occurred mainly during action and rarely during rest.
Dr. Pan and colleagues injected a virus containing GluR(delta)2 protein into the mice’s brains to test the protein’s relationship to tremor. Five days after the injection, the mice’s brains were expressing GluR(delta)2 protein reliably. By 4-6 days after injection, the mice’s tremor had been reduced. It returned to baseline levels at 12-14 days after injection. Injecting a control virus did not affect tremor.
Cerebellar oscillatory indexes were correlated with tremor scores
When the researchers examined local field potentials in mouse cerebellum, they found cerebellar oscillations at 20 Hz that were consistent with the observed tremor. “Putting the evidence together, GluR(delta)2 insufficiency causes CF synaptic pruning deficits, and the surplus CF-PC synaptic activity generates excessive cerebellar oscillations, which drive tremor,” Dr. Pan and colleagues reported.
Next, the researchers performed cerebellar EEG in 10 patients with essential tremor and 10 age-matched controls. Patients had cerebellar oscillations at 4-12 Hz, which are the human tremor frequencies. In an expanded cohort of 20 patients with essential tremor and 20 controls, the cerebellar oscillatory indexes were correlated with tremor scores in patients, which showed that the former could be an index of tremor severity. “Currently, diagnosis of essential tremor is based on pure clinical tremor phenomenology and direct tremor measurement, without a physiological marker indicating the underlying brain circuitry abnormalities,” they wrote. “Cerebellar oscillations can be a physiological signature and a therapeutic target for essential tremor.”
The research was funded by grants from the National Institutes of Health, the Parkinson’s Foundation, the International Essential Tremor Foundation, the Ministry of Science and Technology in Taiwan, and the National Taiwan University Hospital. The authors declared that they had no competing interests.
SOURCE: Pan M-K et al. Sci Transl Med. 2020;12:eaay1769. doi: 10.1126/scitranslmed.aay1769.
FROM SCIENCE TRANSLATIONAL MEDICINE