# Purkinje Cell Rhythmicity, Synchrony, and Enhancing Function in Cerebellar Disorders

> **NIH VA I01** · LOUIS STOKES CLEVELAND VA MEDICAL CENTER · 2021 · —

## Abstract

Because there are so many causes of cerebellar damage (e.g. alcoholism, blast injury, neurodegenerative
diseases, stroke, and simple aging), veterans suffering imbalance, visual impairment, and incoordination
due to cerebellar damage are common. In the past, neurologists had few therapies to improve function in
these patients. Now two emerging ideas in cerebellar physiology hold the promise that better treatments
can be rationally designed. The irregularity hypothesis states that cerebellar dysfunction arises when
cerebellar Purkinje cells (PCs) fire in irregular patterns through loss of their pacemaker properties. It is
cited to explain why drugs that increase PC rhythmicity in vitro such as 4-aminopyridine (4-AP) improve
certain manifestations of cerebellar disease in mice and humans, and it predicts their usefulness in a wide
range of cerebellar disorders. The PC synchrony hypothesis states that synchrony of firing across multiple
PCs determines the effectiveness with which PCs control their synaptic targets, and may explain why PC
irregularity – which could disrupt PC synchrony – is deleterious. If correct, these hypotheses indicate how
laboratory assays can be used to develop more tolerable and effective drugs. If incorrect, their application
to drug development will be futile. Currently, both hypotheses are unproven, and there are data
challenging the applicability of the theory to the flocculus and other regions of the vestibulocerebellum,
even though it was work in the flocculus that led to the irregularity hypothesis in the first place. This
project will address conflicting findings in the literatures on irregularity, 4-AP, and PC synchrony. Like
much previous work on the irregularity hypothesis, parts of the proposal will be conducted in the ataxic
mouse tottering (tg), which carries a mutation in Cacna1a, the gene encoding the ion pore subunit of the
P/Q calcium channel. We focus on the flocculus and its control of reflex eye movements that maintain
clear vision, because their physiology is well understood, because work in this area provides both support
and challenges to the irregularity and synchrony hypotheses, because eye movement and related balance
abnormalities contribute significantly to the symptoms of cerebellar disease, and because successes to
date predict their treatment is possible. Specific Aim 1 will investigate why bath-applied 4-AP restores
regularity of tg vermis PCs in vitro, and oral 4-AP improves tg's performance on the rotarod, but
parenterally administered 4-AP does not improve tg's eye movement deficits that are attributed to
flocculus dysfunction. We will test the possibilities that the conundrum arises through non-validity of the
irregularity hypothesis, or through regional variations in cerebellar physiology, or through differing effects
of chronic oral vs. short-term parenteral exposure to 4-AP. Specific Aim 2 addresses the idea that PC
irregularity disrupts the PC-PC synchrony on which normal cerebellar fu...

## Key facts

- **NIH application ID:** 10337182
- **Project number:** 5I01BX003666-05
- **Recipient organization:** LOUIS STOKES CLEVELAND VA MEDICAL CENTER
- **Principal Investigator:** JOHN SAMUEL STAHL
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337182

## Citation

> US National Institutes of Health, RePORTER application 10337182, Purkinje Cell Rhythmicity, Synchrony, and Enhancing Function in Cerebellar Disorders (5I01BX003666-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10337182. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*