Understanding the relationship between cortical hyperexcitability and the progression of FTD/ALS pathology and behavioral deficits in mice

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that causes severe
personality and behavior changes. A hexanucleotide repeat expansion in the C9orf72 gene is
FTD's most common genetic cause. I aim to elucidate the mechanisms of circuit dysfunction in
C9orf72-FTD, focusing on understanding the relationship between cortical hyperactivity, the
progression of C9orf72 hexanucleotide repeat pathology, and behavior. Understanding these
aspects is crucial for developing effective and timely treatments for FTD.
The first aim of this research is to monitor the progression of neuronal activity during critical age
in a robust animal model of FTD and evaluate its relationship to neuronal loss. In the second
aim, I will determine whether neuronal hyperactivity can causally drive the progression of FTD
pathology and behavioral deficits. I will then test the effect of restoring neuronal activity by
modulating the balance between excitation and inhibition on pathology and behavioral deficits in
a C9orf72-FTD model. I will capitalize on my expertise in state-of-the-art technology, such as
multiphoton microscopy, optogenetics, and chemogenetics while acquiring knowledge and skills
in FTD research, FTD animal models, and electrophysiology.
A team of renowned experts in the field will provide mentorship to guide me through specialized
training and ensure the establishment of an independent research career in the FTD field. The
career development plan includes attending laboratory meetings and departmental discussions,
national conferences, crafting research grant proposals, and preparing manuscripts. The
training will take place at Massachusetts General Hospital (MGH), a prominent teaching hospital
affiliated with Harvard Medical School (HMS). MGH is renowned for its supportive research
environment, advanced resources, and collaborative atmosphere conducive to learning and
research in neurodegenerative diseases. Furthermore, MGH and HMS will facilitate my
professional development by granting me access to various courses and workshops to enhance
my presentation, leadership, and management skills.
In summary, this award will prepare me to lead a research lab, ensuring successful
electrophysiology and FTD/ALS training and an efficient transition to an independent career.

Grant Number: 5K99AG088296-02
NIH Institute/Center: NIH
Principal Investigator: Moustafa Algamal