Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in both the motor cortex and the spinal cord. Currently, there is no curative therapy. The objective of this project is to characterize the mechanisms of ALS pathogenesis, with the long-term goal of identifying new therapeutic targets. Glutamate-induced excitotoxicity of motor neurons is considered a primary mechanism of ALS pathogenesis. While most previous studies have focused on the lack of glutamate transporter as the primary mediator of excitotoxicity, little attention has been paid to a potential alternative cause of excitotoxicity: dysfunctional inhibitor mechanisms. The "cortical hyperexcitability" hypothesis states that degeneration of cortical inhibitory interneurons (CIIN) causes excessive excitability of cortical motor neurons (CMN) and their ultimate degeneration. Despite the existence of this hypothesis for decades, it remains unclear whether CIIN indeed undergo degeneration in ALS, whether loss of CIIN precedes loss of CMN, and whether loss of CIIN results in CMN death. Using an innovative two-photon microscopy system that we designed for in vivo imaging of neuronal morphology in mice, we aim to test the cortical hyperexcitability hypothesis using two mouse models of ALS. Our preliminary studies in ALS mice demonstrated significant loss of dendritic branches in CIIN and marked dendritic blebbing in CMN in the motor cortex, both occurring prior to disease onset. These findings suggest that both CIIN and CMN undergo degeneration in ALS, consistent with the hyperexcitability hypothesis. We propose to test this hypothesis using in vivo microscopy imaging and in vivo functional tests to elucidate the morphological changes of CIIN and the functional consequences of their degeneration in ALS mice. We will:
Aim 1) Determine if CIIN degeneration is an initiating factor in ALS pathogenesis, through in vivo imaging in ALS mouse models;
and Aim 2) Determine if ablation of CIIN in the motor cortex causes CMN death and accelerates ALS disease progression. Successful completion of this project will establish a foundation for understanding the role of CIIN in ALS pathogenesis, paving the way for future research targeting CIIN as a novel therapeutic for ALS.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive loss of motor neurons in both the motor cortex and the spinal cord. No curative therapy currently exists. We will determine whether, when, and how degeneration of neurons takes place in the motor cortex using mouse models of ALS. Our results will identify key mechanisms of ALS pathogenesis, paving the way for future development of novel therapeutics for ALS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS075382-01A1
Application #
8510018
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gubitz, Amelie
Project Start
2013-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
1
Fiscal Year
2013
Total Cost
$218,750
Indirect Cost
$93,750
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609