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Essential tremor (ET) is among the most prevalent movement disorders, but its origins are elusive. The inferior olivary nucleus (ION) has been hypothesized as the prime generator of tremor because of the pacemaker properties of ION neurons, but structural and functional changes in ION are unlikely under ET. Abnormalities have instead been reported in the cerebello-thalamo-cortical network, including dysfunctions of the GABAergic projections from the cerebellar cortex to the dentate nucleus. It remains unclear, though, how tremor would relate to a dysfunction of cerebellar connectivity. To address this question, we built a computational model of the cortico-cerebello-thalamo-cortical loop. We simulated the effects of a progressive loss of GABA A α 1 -receptor subunits and up-regulation of α 2/3 -receptor subunits in the dentate nucleus, and correspondingly, we studied the evolution of the firing patterns along the loop. The model closely reproduced experimental evidence for each structure in the loop. It showed that an alteration of amplitudes and decay times of the GABAergic currents to the dentate nucleus can facilitate sustained oscillatory activity at tremor frequency throughout the network as well as a robust bursting activity in the thalamus, which is consistent with observations of thalamic tremor cells in ET patients. Tremor-related oscillations initiated in small neural populations and spread to a larger network as the synaptic dysfunction increased, while thalamic high-frequency stimulation suppressed tremor-related activity in thalamus but increased the oscillation frequency in the olivocerebellar loop. These results suggest a mechanism for tremor generation under cerebellar dysfunction, which may explain the origin of ET.
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The effect of extracellular potassium concentration on the oscillation frequency of the pacemaker nucleus in the weakly electric fish Apteronotus leptorhynchus
Abstract The weakly electric brown ghost knifefish (Apteronotus leptorhynchus) exhibits a pronounced sexual dimorphism in its electric behavior—males discharge at higher frequencies than females, with little overlap between the sexes. The frequency of these electric organ discharges is controlled by the frequency of the synchronized oscillations of the medullary pacemaker nucleus. Previous studies have suggested that sex-specific differences in the morphology and gene expression pattern of the astrocytic syncytium that envelopes the pacemaking neural network cause differences in its capacity to buffer the extracellular concentration of K+. This change in the K+buffering capacity affects the K+equilibrium potential of the neurons constituting the neural network, which in turn modulates the frequency of the pacemaker nucleus. In the present study, we have tested a critical element of this hypothesis by examining whether, and how, changes in the extracellular K+concentration influence the frequency of the pacemaker nucleus oscillations. By using an in vitro preparation of the pacemaker nucleus, the results of this investigation demonstrate that exposure of this nucleus to acutely increased/decreased concentrations of K+in the perfusate (while maintaining osmolarity) leads to concentration-dependent increases/decreases in the frequency of the synchronized oscillations generated by the pacemaker nucleus.
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- PAR ID:
- 10550403
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- Journal of Comparative Physiology A
- Volume:
- 211
- Issue:
- 1
- ISSN:
- 0340-7594
- Format(s):
- Medium: X Size: p. 113-121
- Size(s):
- p. 113-121
- Sponsoring Org:
- National Science Foundation
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