Serotonin and the 5-HT2B Receptor in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the major adult onset motor neuron disease characterized by progressive muscle paralysis and spasticity leading ultimately to death of the patient within 2 to 5 years after onset. ALS is typically associated with degeneration of upper and lower motor neurons. Degeneration of brainstem serotonin neurons has recently been demonstrated in both ALS patients and mouse models, and was found responsible for the development of spasticity, once thought to be caused by the sole impairment of the corticospinal tract. Consistent with involvement of central serotonin pathways, the 5-HT2B receptor was found upregulated in microglia of ALS mice. Its deletion worsened disease outcome in a mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene was associated with survival in patients as well as microglial degeneration. As a whole, these studies suggest that the clinical phenotype of ALS patients is partially caused by the degeneration of serotonergic neurons and that microglial 5-HT2B receptor is critical for survival of this cell type in ALS spinal cord.