# Understanding Degeneration in Neurons of the Inferior Olivary Nucleus

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $509,145

## Abstract

The inferior olivary nucleus plays a vital role in cerebellar function and motor control, and olivary degeneration
is central to the pathophysiology of tremor and ataxia. A striking feature of olivary neurons is that they are
susceptible to degeneration both from intrinsic molecular pathology (e.g., in spinocerebellar ataxias) as well as
from extrinsic denervation of inhibitory cerebellar input which causes hypertrophic olivary degeneration (HOD).
These triggers for olivary degeneration are assumed to reflect distinct cell death mechanisms, but our recent
data strongly suggests that these different etiologies utilize shared molecular events key to olivary neuron
viability. This proposal will test this novel hypothesis, which has profound implications for inferior olivary neuron
survival and function. In a genetically precise mouse model of spinocerebellar ataxia type 1 (SCA1; SCA1-
knockin or SCA1-KI mice), we find olivary neuron hypertrophy accompanied by the characteristic increase in
dendrite length. Remarkably, these features occur in the absence of loss of inhibitory input. Moreover, we find
no olivary pathology in a separate line of SCA1 transgenic mice that exhibit more severe but restricted
cerebellar Purkinje neuron degeneration. A significant loss of calbindin positive neurons, characteristic of
olivary degeneration, accompanies HOD in SCA1-KI mice. Considered together, these findings challenge
current dogma by dissociating HOD and denervation. Preliminary studies using in vivo electrophysiological
recordings demonstrate that synaptic (extrinsic) excitation on the olive, the cause of HOD due to inhibitory
neuron denervation, is not increased. Additional studies demonstrate that hypertrophic olivary neurons exhibit
increased intrinsic excitability of neurons due to potassium (K+) channel loss-of-function. Based on these
findings, we hypothesize that this increased intrinsic excitability is the trigger for olivary degeneration in SCA1,
and that increased excitability from whatever source (intrinsic or extrinsic) is a shared mechanism for inferior
olive degeneration. We further hypothesize that olivary degeneration can therefore be prevented by
normalizing membrane excitability. We will test these hypotheses through the following Specific Aims: Aim 1.
Define the relationship between membrane excitability and olivary degeneration in SCA1. Aim 2: Define
intrinsic and extrinsic contributions to olivary dysfunction in models of SCA1. Aim 3: Determine the basis for
increased intrinsic excitability in hypertrophic olivary degeneration in SCA1. Results from these studies are
expected to establish that increased membrane excitability is a convergent mechanism for olivary
degeneration. These studies would be expected to provide insight into whether neuronal degeneration due to
synaptic excitotoxicity may be addressed by reducing intrinsic excitability as a therapeutic strategy.

## Key facts

- **NIH application ID:** 10980254
- **Project number:** 1R01NS128285-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Vikram Govindaraju Shakkottai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $509,145
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980254

## Citation

> US National Institutes of Health, RePORTER application 10980254, Understanding Degeneration in Neurons of the Inferior Olivary Nucleus (1R01NS128285-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10980254. Licensed CC0.

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