Altered network properties in C9ORF72 repeat expansion cortical neurons are due to synaptic dysfunction

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Cortical network dysfunction is widespread in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), particularly in patients with the C9ORF72 repeat expansion (C9ORF72^RE) mutation.
• This dysfunction is evident pre-symptomatically and is thought to drive neurodegenerative progression, but the underlying cellular and molecular mechanisms remain unclear.

Purpose of the Study:

• To investigate the cellular and molecular mechanisms of cortical network dysfunction in ALS and FTD caused by the C9ORF72^RE mutation.
• To establish a model of network activity in patient-derived neurons and examine physiological processes.

Main Methods:

• Generated induced pluripotent stem cell (iPSC)-derived cortical neurons from C9ORF72^RE patients and isogenic controls.
• Utilized multi-electrode array electrophysiology to model network activity.
• Employed patch-clamp electrophysiology, immunocytochemistry, pharmacology, and transcriptomic profiling (RNA-seq) for mechanistic examination.

Main Results:

• C9ORF72^RE leads to elevated network burst activity and enhanced synaptic input, but reduced burst duration due to impaired pre-synaptic vesicle dynamics.
• Demonstrated impaired synaptic plasticity and identified dysregulated molecular pathways affecting synaptic function via RNA-seq.
• Observed complete rescue of all deficits upon CRISPR/Cas9 correction of the C9ORF72^RE mutation.

Conclusions:

• Synaptic pathophysiology is a widespread and early driver of altered network function in ALS-FTD.
• Identified novel defects in pre- and post-synaptic compartments, including synaptic plasticity and vesicle dynamics, impacting cortical function and neurodegeneration.