# Motoneuron mortality in neurodegenerative diseases induced by homeostatic dysregulation of excitability

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2022 · $552,803

## Abstract

Multiple mechanisms has been proposed for the selective vulnerability of motoneurons in neurodegenerative
diseases. In reflecting on the prior work from our laboratories, as well as that of our colleagues around the
world, we have developed a synthetic hypothesis that accounts for a vast majority of the reported findings. We
propose that the net response of mouse motoneurons to the presence of mutant proteins is a disregulation of
homeostatic plasticity. This manifests as an increased `gain' of both the up- and down-regulation of
compensatory mechanisms designed to control the level of motoneuronal activity. The toxic increase of gain
function leads to overcompensation and a dramatic cascade of homeostatic oscillations that increases
motoneuron morbidity. Further, we propose that size-scaling of these compensatory mechanisms leads to the
observed greater vulnerability of the largest motoneurons. The goal of this project is to provide rigorous testing
of this novel disregulation hypothesis using mutant SOD1 mice as a model system for neurodegenerative
diseases that disproportionately target motoneurons. The proposed experiments rest heavily on our recent
technical breakthroughs that enable us to perform intracellular recordings of mouse motoneurons throughout
disease progression, from neonate through adult, using both in vivo and in vitro preparations, as well as our
expertise in assessing the density and spatial distributions of membrane channels in motoneurons. Our
approach entails presenting a series of `homeostatic challenges' to motoneuron excitability and comparing the
compensatory responses of mSOD1 motoneurons to those of wild-type controls. If our hypothesis is correct,
we expect to observe that mSOD1 motoneurons exhibit consistently greater responses to each of the
challenges than do wild-types and that these mSOD1 responses scale with motoneuron size. There are three
specific aims: to assess the responses of mSOD1 and control motoneurons to drug perturbations that alter the
intrinsic electrical properties of motoneurons (Aim 1), the synaptic inputs to motoneurons (Aim 2) and the
neuromodulatory inputs to motoneurons (Aim 3). The resulting data will provide a strong impetus for pursuing
radical, novel therapeutic strategies as well as for elucidating the specific signal transduction cascades
underlying the different homeostatic mechanisms.

## Key facts

- **NIH application ID:** 10433844
- **Project number:** 5R01NS110953-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** MARC D BINDER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $552,803
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433844

## Citation

> US National Institutes of Health, RePORTER application 10433844, Motoneuron mortality in neurodegenerative diseases induced by homeostatic dysregulation of excitability (5R01NS110953-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10433844. Licensed CC0.

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