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Increased Purkinje Cell Complex Spike and Deep Cerebellar Nucleus Synchrony as a Potential Basis for Syndromic Essential Tremor. A Review and Synthesis of the Literature

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Abstract

We review advances in understanding Purkinje cell (PC) complex spike (CS) physiology that suggest increased CS synchrony underlies syndromic essential tremor (ET). We searched PubMed for papers describing factors that affect CS synchrony or cerebellar circuits potentially related to tremor. Inferior olivary (IO) neurons are electrically coupled, with the degree of coupling controlled by excitatory and GABAergic inputs. Clusters of coupled IO neurons synchronize CSs within parasagittal bands via climbing fibers (Cfs). When motor cortex is stimulated in rats at varying frequencies, whisker movement occurs at ~10 Hz, correlated with synchronous CSs, indicating that the IO/CS oscillatory rhythm gates movement frequency. Intra-IO injection of the GABAA receptor antagonist picrotoxin increases CS synchrony, increases whisker movement amplitude, and induces tremor. Harmaline and 5-HT2a receptor activation also increase IO coupling and CS synchrony and induce tremor. The hotfoot17 mouse displays features found in ET brains, including cerebellar GluRδ2 deficiency and abnormal PC Cf innervation, with IO- and PC-dependent cerebellar oscillations and tremor likely due to enhanced CS synchrony. Heightened coupling within the IO oscillator leads, through its dynamic control of CS synchrony, to increased movement amplitude and, when sufficiently intense, action tremor. Increased CS synchrony secondary to aberrant Cf innervation of multiple PCs likely also underlies hotfoot17 tremor. Deep cerebellar nucleus (DCN) hypersynchrony may occur secondary to increased CS synchrony but might also occur from PC axonal terminal sprouting during partial PC loss. Through these combined mechanisms, increased CS/DCN synchrony may plausibly underlie syndromic ET.

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Acknowledgments

We thank Hovsep Kosoyan, Ph.D. for assistance in figure preparation.

Funding

Supported by International Essential Tremor Foundation and by Veterans Affairs (A.H.), and by a NIH/NINDS grant R21NS101386 (E.J.L.).

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Authors and Affiliations

  1. Neurology Service, Veterans Affairs Greater Los Angeles Healthcare System, 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA

    Adrian Handforth

  2. Department of Neuroscience and Physiology, New York University, School of Medicine, New York, NY, USA

    Eric J. Lang

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Contributions

The first draft and literature search were performed by A.H. Both E.J.L. and A.H. contributed conceptually and to critical revisions of the work.

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Correspondence to Adrian Handforth.

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Conflict of Interest

A.H. has received funding for clinical trials from Eisai, Medtronic, and Sonexa, and is on the Medical Board of the International Essential Tremor Foundation. E.J.L. declares no conflicts of interest.

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Handforth, A., Lang, E.J. Increased Purkinje Cell Complex Spike and Deep Cerebellar Nucleus Synchrony as a Potential Basis for Syndromic Essential Tremor. A Review and Synthesis of the Literature. Cerebellum 20, 266–281 (2021). https://doi.org/10.1007/s12311-020-01197-5

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