C9orf72 hexanucleotide repeat expansion leads to altered neuronal and dendritic spine morphology and synaptic...

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder with no effective therapies.
• The C9orf72 hexanucleotide repeat expansion (C9-HRE) is the most common genetic cause of FTLD and amyotrophic lateral sclerosis (ALS).
• FTLD involves neurotransmitter system dysregulation, impacting neuronal function.

Purpose of the Study:

• To investigate the impact of the C9-HRE on synaptic function, molecular composition, and dendritic spine morphology.
• To understand the mechanisms underlying synaptic changes in C9-HRE-associated FTLD.

Main Methods:

• Overexpression of the pathological C9-HRE in cultured mouse hippocampal neurons.
• Biochemical assays, confocal microscopy, and live cell calcium imaging to assess pathological, morphological, and functional changes.
• Analysis of RNA foci, DPR proteins, dendritic spine morphology, neuronal branching, and excitotoxicity.

Main Results:

• C9-HRE expression induced pathological RNA foci and DPR proteins.
• Significant alterations in dendritic spine morphology (decreased mushroom, increased stubby/thin spines) and reduced neuronal branching were observed.
• Neurons with C9-HRE showed increased susceptibility to glutamate excitotoxicity and prolonged responses to excitatory stimuli, linked to enhanced extrasynaptic GluN2B-NMDA receptor activity.

Conclusions:

• The C9-HRE is associated with enhanced excitotoxicity and synaptic dysfunction.
• Therapeutic strategies targeting synaptic disturbances could be effective for treating C9-HRE-associated FTLD.