Inhibitory interneurons show early dysfunction in a SOD1 mouse model of ALS

Abstract

AbstractFew studies in amyotrophic lateral sclerosis (ALS) focus on the premotor interneurons synapsing onto motoneurons (MNs). We hypothesized inhibitory interneurons contribute to dysfunction, particularly if altered before MN neuropathology. We directly assessed excitability and morphology of ventral lumbar glycinergic interneurons from SOD1G93AGlyT2eGFP (SOD1) and wildtype GlyT2eGFP (WT) mice. SOD1 interneurons were smaller but density was unchanged. Patch clamp revealed dampened excitability in SOD1 interneurons, including depolarized PICs and voltage threshold. Renshaw cells (RCs; confirmed with immunohistochemistry) showed similar dampened excitability. Morphology and electrophysiology were used to create a “random forest” statistical model to predict RCs when histological verification was not possible. Predicted SOD1 RCs were less excitable (consistent with experimental results); predicted SOD1 non-RCs were more excitable. In summary, inhibitory interneurons show very early perturbations poised to impact MNs, modify motor output, and provide early biomarkers of ALS. Therapeutics like riluzole that universally reduce CNS excitability could exacerbate this dysfunction.