Project Overview
Brain activity depends on a delicate balance between excitation and inhibition. When this balance is disrupted, brain cells can become abnormally overactive, a feature shared by many neurological disorders, including amyotrophic lateral sclerosis (ALS). While most research has focused on how neurons themselves control this balance, much less attention has been paid to the environment that surrounds them.
About one quarter of the brain is made up of the extracellular space, the fluid-filled region between cells. This space is structured by the extracellular matrix, a mesh of molecules that supports brain cells and helps organize communication between them. Emerging evidence suggests that the extracellular matrix does more than provide structural support. It may actively regulate the levels of key ions, such as chloride and potassium, that control how neurons respond to inhibitory signals. However, until now, these extracellular ionic environments have been extremely difficult to measure. In ALS, changes in brain activity occur early, before extensive neuron loss. In particular, inhibitory neurons that normally keep brain activity in check lose specialized extracellular matrix structures that surround them. We propose that this breakdown disrupts the brain’s ability to control local ion levels, weakening inhibition and allowing excessive activity to develop.
In this project, we will use advanced optical imaging techniques to directly measure ion concentrations in the brain at high resolution, while carefully altering the extracellular matrix in healthy and ALS mouse models. By combining these measurements with computational modeling, we aim to reveal how the extracellular environment shapes neuronal activity in health and disease. By identifying the extracellular matrix as an active regulator of brain inhibition, this research opens new possibilities for treating neurological disorders. Instead of targeting neurons alone, future therapies may restore healthy brain activity by stabilizing the extracellular environment that supports inhibitory control.
Partners & Donors
Allan Kliger and friends
