Microscale dysfunction and mesoscale compensation in degenerating neuronal networks

Area of Science:

• Neuroscience
• Systems Biology
• Computational Neuroscience

Background:

• Neurodegenerative diseases share features like neuronal dysfunction and compensatory network mechanisms.
• Compensatory processes, such as network centralization, are less understood in amyotrophic lateral sclerosis (ALS).

Purpose of the Study:

• To investigate structural and functional network properties in ALS patient-derived motor neurons.
• To determine if ALS exhibits compensatory centralization similar to other neurodegenerative diseases.

Main Methods:

• Longitudinal multielectrode array recordings of ALS and healthy control motor neuron networks.
• Graph theory-based analysis to assess network structure and function.
• Investigation of TAR DNA-binding protein 43 (TDP-43) proteinopathy.

Main Results:

• Observed microscale dysfunction in ALS networks: TDP-43 proteinopathy, hyperactivity, and reduced spike amplitude.
• Detected structural changes: neurite hypertrophy suggesting attempts at new connections.
• Revealed mesoscale functional reconfigurations: increased rich-club connectivity and assortativity, indicating compensatory centralization.

Conclusions:

• ALS network features can be modeled in vitro.
• ALS networks progressively centralize to maintain computational capacity, increasing hub node vulnerability.
• Supports common network reconfiguration mechanisms across neurodegenerative diseases.