Is essential tremor a disorder of GABA dysfunction? No

Steven Bellows, Joohi Jimenez-Shahed

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

Abstract

Although essential tremor is common, its underlying pathophysiology remains uncertain, and several hypotheses seek to explain the tremor mechanism. The GABA hypothesis states that disinhibition of deep cerebellar neurons due to reduced GABAergic input from Purkinje cells results in increased pacemaker activity, leading to rhythmic output to the thalamo-cortical circuit and resulting in tremor. However, some neuroimaging, spectroscopy, and pathology studies have not shown a clear or consistent GABA deficiency in essential tremor, and animal models have indicated that large reductions of Purkinje cell inhibition may improve tremor. Instead, tremor is increasingly attributable to dysfunction in oscillating networks, where altered (but not necessarily reduced) inhibitory signaling can result in tremor. Hypersynchrony of Purkinje cell activity may account for excessive oscillatory cerebellar output, with potential contributions along multiple sites of the olivocerebellar loop. Although older animal tremor models, such as harmaline tremor, have explored contributions from the inferior olivary body, increasing evidence has pointed to the role of aberrant climbing fiber synaptic organization in oscillatory cerebellar activity and tremor generation. New animal models such as hotfoot17j mice, which exhibit abnormal climbing fiber organization due to mutations in Grid2, have recapitulated many features of ET. Similar abnormal climbing fiber architecture and excessive cerebellar oscillations as measured by EEG have been found in humans with essential tremor. Further understanding of hypersynchrony and excessive oscillatory activity in ET phenotypes may lead to more targeted and effective treatment options.

Original languageEnglish
Title of host publicationEssential Tremor
Subtitle of host publicationCurrent Concepts and Controversies
EditorsSheng-Han Kuo, Elan D. Louis
PublisherAcademic Press Inc.
Pages285-310
Number of pages26
ISBN (Print)9780323899741
DOIs
StatePublished - Jan 2022

Publication series

NameInternational Review of Neurobiology
Volume163
ISSN (Print)0074-7742
ISSN (Electronic)2162-5514

Keywords

  • Deep cerebellar nuclei
  • GABA hypothesis
  • Hypersynchrony
  • Inferior olivary body
  • Olivocerebellar
  • Purkinje cell
  • Tremor

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