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Spinal inhibitory interneurons could contribute to amyotrophic lateral sclerosis (ALS) pathology, but their excitability has never been directly measured. We studied the excitability and morphology of glycinergic interneurons in early postnatal transgenic mice (SOD1Few studies in amyotrophic lateral sclerosis (ALS) measure effects of the disease on inhibitory interneurons synapsing onto motoneurons (MNs). However, inhibitory interneurons could contribute to dysfunction, particularly if altered before MN neuropathology, and establish a long-term imbalance of inhibition / excitation. We directly assessed excitability and morphology of glycinergic (GlyT2 expressing) ventral lumbar interneurons from SOD1G93AGlyT2eGFP (SOD1) and wildtype GlyT2eGFP (WT) mice on postnatal days 6-10. Patch clamp revealed dampened excitability in SOD1 interneurons, including depolarized persistent inward currents (PICs), increased voltage and current threshold for firing action potentials, along with a marginal decrease in afterhyperpolarization (AHP) duration. Primary neurites of ventral SOD1 inhibitory interneurons were larger in volume and surface area than WT. GlyT2 interneurons were then divided into 3 subgroups based on location: (1) interneurons within 100 μm of the ventral white matter, where Renshaw cells (RCs) are located, (2) interneurons interspersed with MNs in lamina IX, and (3) interneurons in the intermediate ventral area including laminae VII and VIII. Ventral interneurons in the RC area were the most profoundly affected, exhibiting more depolarized PICs and larger primary neurites. Interneurons in lamina IX had depolarized PIC onset. In lamina VII-VIII, interneurons were least affected. 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. Abstract figure legend SOD1 glycinergic interneurons in the ventral horn show altered morphology and excitability, including depolarization of PICs, depolarized threshold, shorter AHPs, smaller somata and larger primary neurites. Ventrally located interneurons are the most prominently affected. This article is protected by copyright. All rights reserved.

Although they share the common function of controlling muscle fiber contraction, spinal motoneurons display a remarkable diversity. Alpha-motoneurons are the "final common pathway", which relay all the information from spinal and supraspinal centers and allow the organism to interact with the outside world by controlling the contraction of muscle fibers in the muscles. On the other hand, gamma-motoneurons are specialized motoneurons that do not generate force and instead specifically innervate muscle fibers inside muscle spindles, which are proprioceptive organs embedded in the muscles. Beta-motoneurons are hybrid motoneurons that innervate both extrafusal and intrafusal muscle fibers. Even among alpha-motoneurons, there exists an exquisite diversity in terms of motoneuron electrical and molecular properties, physiological and structural properties of their neuromuscular junctions, and molecular and contractile properties of the innervated muscle fibers. This diversity, across species, across muscles, and across muscle fibers in a given muscle, underlie the vast repertoire of movements that one individual can perform.

Spinal alpha-motoneurons are classified in several types depending on the contractile properties of the innervated muscle fibers. This diversity is further displayed in different levels of vulnerability of distinct motor units to neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS). We summarize recent data suggesting that, contrary to the excitotoxicity hypothesis, the most vulnerable motor units are hypoexcitable and experience a reduction in their firing prior to symptoms onset in ALS. We suggest that a dysregulation of activity-dependent transcriptional programs in these motoneurons alter crucial cellular functions such as mitochondrial biogenesis, autophagy, axonal sprouting capability and re-innervation of neuromuscular junctions.