# Mechanistic insights of cortical hyperexcitability in ALS

> **NIH NIH R21** · EMORY UNIVERSITY · 2024 · $75,699

## Abstract

PROJECT SUMMARY/ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease caused by the loss of upper
and lower motor neurons, leading to progressive muscle weakness and paralysis. Many altered molecular and
cellular pathways have been implicated in disease pathogenesis. However, determining which are causative
remains challenging, and many clinical trials have failed in the last few decades. One explanation for the
unsuccessful clinical interventions is the difficulty of rescuing dying motor neurons once death has been
triggered, meaning that therapeutic interventions must be implemented early in the disease. Months before
clinical onset, ALS patients often experience fasciculations and cramps (i.e., spontaneous and persistent
muscle twitching), suggesting increased neural activity and excitability. Indeed, neurophysiological studies in
patients and rodent models with ALS-associated genetic mutations have identified that circuit dysfunction,
specifically motor cortex hyperexcitability, are among the earliest pathologies. Recently, two studies suggested
that upper corticospinal motor neurons (CSMN) in the motor cortex play an essential role in the low motor
neuron death of transgenic mice expressing human SOD1 mutations. We thus hypothesize that CSMN
hyperexcitability might drive ALS pathogenesis. We propose to utilize recently developed enhancer-driven viral
tools that allow cell-specific targeting to 1) perform cutting-edge chemogenetics to modulate neuronal activity
to determine whether dampening CSMN hyperexcitability in the late pre-symptomatic stage can mitigate ALS-
related behavioral and pathological deficits in SOD1G93A mice, and 2) identify cell-specific altered molecular
pathways leading to motor cortex hyperexcitability. This study has significant implications in developing
therapeutics targeting this early clinical abnormality in ALS patients.

## Key facts

- **NIH application ID:** 10986723
- **Project number:** 3R21NS133960-01S1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Jie Jiang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $75,699
- **Award type:** 3
- **Project period:** 2023-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10986723

## Citation

> US National Institutes of Health, RePORTER application 10986723, Mechanistic insights of cortical hyperexcitability in ALS (3R21NS133960-01S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10986723. Licensed CC0.

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