Project Overview
Frontotemporal dementia (FTD) is a progressive brain disorder that primarily affects thinking, behavior, and social interactions. It is the most common form of dementia in adults under 65 and places a heavy burden on patients, families, and healthcare systems. Despite this, we still lack effective treatments, partly because the brain mechanisms that cause symptoms are poorly understood. One early feature of many neurodegenerative diseases, including FTD, is overactivity, known as hyperexcitability. Normally, specialized inhibitory neurons called parvalbumin (PV) and somatostatin (SST) interneurons prevent overactivity in brain circuits, keeping neural communication balanced. In our previous work on amyotrophic lateral sclerosis (ALS), we discovered that these interneurons can fail and that a protein called KCC2, which helps maintain proper chloride levels in neurons and allows inhibition to work effectively, is often reduced. Restoring KCC2 or boosting interneuron function in ALS mice normalized brain activity and improved outcomes. Building on this foundation, we will test whether a similar breakdown of inhibition occurs in FTD, focusing on the medial prefrontal cortex (mPFC), a brain region important for decision-making, flexibility, and social behavior. Using a mouse model of FTD, we will monitor activity in PV and SST neurons and the main excitatory cells (pyramidal neurons) in the mPFC.
We will measure whether KCC2 levels and function are reduced and whether this contributes to overactive circuits. Finally, we will test whether boosting KCC2 function with a safe, FDA-approved drug (prochlorperazine) can restore the balance of brain activity and improve cognitive and social behaviors in FTD mice. This work will identify the specific cell types and mechanisms that fail in FTD and evaluate the potential therapeutic targets the underlying cause of circuit dysfunction. Ultimately, results from this work may identify interventions to slow cognitive decline, improve quality of life, and reduce the burden on patients and caregivers.
Partners & Donors
Azrieli Foundation
