Sensory neuron dysfunction and hyperexcitability in dorsal root ganglia at disease onset in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is widely known for its impact on motor neurons, but recent research has revealed that sensory neurons in the dorsal root ganglia (DRG) also play a significant role in the disease. To explore this, scientists examined DRG pathology in 12-week-old SOD1G93A mice, a model for ALS. Using a combination of transcriptomics, morphology, and electrophysiology, they discovered that sensory neurons showed distinct early molecular and functional alterations.

Genetic analysis of lumbar DRG revealed 35 differentially expressed genes, predominantly upregulated, many of which were linked to oxidative stress and phagosome pathways. This suggests the sensory neurons respond uniquely to the disease process, setting themselves apart from motor neuron gene expression patterns. Morphologically, both A- and C-fiber DRG neurons were smaller, indicating potential damage or dysfunction.

Interestingly, the distribution of sodium channels, Nav1.7 and Nav1.8, changed. Nav1.7 increased in A fibers, while Nav1.8 levels rose in both A and C fibers, while Nav1.6 remained stable. This shift in sodium channel expression is a hallmark of heightened neuronal excitability.

Electrophysiological recordings further supported these findings. A-fiber neurons displayed a depolarized resting membrane potential, higher spike amplitudes, and more frequent repetitive firing, indicative of hyperexcitability. C fibers, however, did not exhibit these changes, suggesting the hyperexcitability is limited to A-fiber sensory neurons.

These combined results paint a comprehensive picture of early sensory neuron dysfunction in ALS, extending beyond the well-studied motor neuron pathology. This study not only confirms the presence of sensory system involvement in ALS but also highlights sensory neuron excitability as a promising therapeutic target for the disease.