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

Abstract

Few studies in amyotrophic lateral sclerosis (ALS) focus on the inhibitory interneurons synapsing onto motoneurons (MNs). However, inhibitory interneurons could contribute to dysfunction, particularly if altered before MN neuropathology and establishing a long-term imbalance of inhibition / excitation. We directly assessed excitability and morphology of glycinergic (GlyT2) interneurons located throughout the ventral horn in the lumbar enlargement from SOD1^G93AGlyT2eGFP (SOD1) and wildtype GlyT2eGFP (WT) mice on postnatal day 6 to 10. Patch clamp revealed dampened excitability in SOD1 interneurons, including depolarized persistent inward currents (PICs), depolarized threshold for firing action potentials, and a shortened afterhyperpolarization (AHP). SOD1 inhibitory interneurons also had smaller soma but increased dendritic volume and surface area. GlyT2 interneurons were then divided into 3 subgroups based on location: interneurons within 100 μm of the ventral white matter where Renshaw cells (RCs) are located, interneurons interspersed with MNs in lamina IX, and interneurons in the intermediate ventral area including laminae VII and VIII. Lamina IX interneurons were the most profoundly affected, including more depolarized PICs, smaller somata and larger dendritic arborization. Interneurons in lamina IX had depolarized PIC onset, smaller somata and longer dendrites. In lamina VII-VIII, interneurons were largely unaffected, mainly showing smaller somata. In summary, inhibitory interneurons show very early region-specific perturbations poised to impact excitatory / inhibitory balance of MNs, modify motor output, and provide early biomarkers of ALS. Therapeutics like riluzole which universally reduce CNS excitability could exacerbate the inhibitory dysfunction described here.