# Serotoninergic modulation of cerebellar circuitry

> **NIH NIH F31** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $22,760

## Abstract

Project Summary/Abstract
 Ataxia (uncoordinated movement) is a debilitating disorder that interferes patients' ability to perform
activities of daily living. Ataxia is caused by dysfunction of the cerebellum, a brain area involved in motor
coordination and maintenance of balance. There are few therapies available for treatment of ataxia, and the
ones used, such as serotoninergic agents, have limited efficacy often only in a subset of patients. Thus, there
is a real need for new and improved therapeutic approaches for the management and treatment of ataxia.
 A major cause of cerebellar dysfunction is abnormal Purkinje cell activity. Purkinje cells, the sole output
of the cerebellar cortex, are intrinsically active cells that integrate synaptic input from over 150,000 parallel
fiber synapses and one climbing fiber. Serotonin (5-HT) has excitatory, inhibitory, or biphasic effects on firing
rate of Purkinje cells. Similarly, serotonin depresses and potentiates parallel fiber-Purkinje cell synaptic
transmission, and affects the climbing fiber-Purkinje cell synaptic transmission. The mechanisms by which
serotonin causes these opposing effects are not understood. Nevertheless, because serotoninergic drugs are
promising for the treatment of ataxia, it is important to delineate the mechanism by which they modulate
cerebellar function. Serotoninergic drugs that have been most efficacious in lessening motor dysfunction were
chosen to target the 5-HT1A receptor. However, these drugs can also activate 5-HT7 receptors. In the
cerebellar cortex, 5-HT1A and 5-HT7 receptors are localized only to Purkinje cells and parallel fibers. Because
5-HT1A and 5-HT7 receptors typically have opposing effects on firing and synaptic transmission, it is plausible
that the limited efficacy of serotoninergic drugs used to treat ataxia is due to activation of multiple receptors
that elicit opposing effects on cerebellar function. Thus, in order to improve the therapeutics for ataxia, it is
important to delineate how serotonin alters cerebellar function. The goal of this proposal is to elucidate how
selective activation of 5-HT1A and 5-HT7 receptors alters Purkinje cell intrinsic firing and excitatory synaptic
transmission onto Purkinje cells. To do so, this proposal uses electrophysiology to record from Purkinje cells in
acutely prepared cerebellar slices. Aim 1 elucidates how selective 5-HT1A and 5-HT7 receptor activation
affects Purkinje cell intrinsic firing. In addition, we will examine the therapeutic efficacy of selective serotonergic
agonists that alter Purkinje cell activity in a mouse model of spinocerebellar ataxia type 3. Aim 2 delineates the
effect of selective 5-HT1A and 5-HT7 receptor activation on parallel fiber and climbing fiber synaptic
transmission, the pre- or post-synaptic components of any potential modulation, and long-term plasticity.
Successful completion of this proposal will reveal the actions of clinically-relevant serotoninergic receptors and
shed ligh...

## Key facts

- **NIH application ID:** 9899327
- **Project number:** 5F31NS105406-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Kristin Palarz
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $22,760
- **Award type:** 5
- **Project period:** 2018-03-01 → 2020-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899327

## Citation

> US National Institutes of Health, RePORTER application 9899327, Serotoninergic modulation of cerebellar circuitry (5F31NS105406-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899327. Licensed CC0.

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