Developmental circuit instability in amyotrophic lateral sclerosis: from hyperexcitability to network collapse

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Amyotrophic lateral sclerosis (ALS) is typically seen as a late-onset motor neuron disease.
• The origins of cortical dysfunction in ALS pathogenesis are not fully understood.

Purpose of the Study:

• To investigate the developmental trajectory of cortical networks in SOD1G93A mice.
• To identify early cellular and network mechanisms underlying ALS pathogenesis.

Main Methods:

• Multimodal approach: morphometrics, electrophysiology, pharmacology, molecular analysis, computational modeling, and machine learning.
• Analysis of cultured cortical networks from SOD1G93A mouse embryos.
• In silico modeling to identify drivers of hyperexcitability.

Main Results:

• ALS neurons exhibit impaired maturation, connectivity, and a transient hyperexcitability phase.
• Early astrocytic dysfunction impairs neuronal synchronization, linking glial issues to instability.
• Synaptic transmission shows an excitatory bias, maladaptive inhibition, and GABA/glutamate co-release.
• Deficient intrinsic adaptation identified as a key driver of hyperexcitability.

Conclusions:

• ALS is a developmentally rooted disorder of cortical network homeostasis, driven by glial, synaptic, and intrinsic adaptation failures.
• Cortical dysfunction precedes neurodegeneration, establishing a link between early network instability and disease progression.
• Electrophysiological network signatures detected by machine learning are potential biomarkers for early ALS diagnosis and therapeutic screening.