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bioRxiv · 10.1101/2020.10.21.348359

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

Cavarsan, C. F.·Steele, P. R.·McCane, L. M.·LaPre, K. J.·Puritz, A. C.·Katenka, N.·Quinlan, K. A.
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Abstract

Few 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 m 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/348359v4_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@1dde8beorg.highwire.dtl.DTLVardef@1db13edorg.highwire.dtl.DTLVardef@1f95cbeorg.highwire.dtl.DTLVardef@37ec18_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOAbstract Figure:C_FLOATNO 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. C_FIG Key Points SummaryO_LISpinal inhibitory interneurons could contribute to amyotrophic lateral sclerosis (ALS) pathology, but their excitability has never been directly measured. C_LIO_LIWe studied the excitability and morphology of glycinergic interneurons in early postnatal transgenic mice (SOD1G93AGlyT2eGFP). C_LIO_LIInterneurons were less excitable and had marginally smaller somas but larger primary neurites in SOD1 mice. C_LIO_LIGlyT2 interneurons were analyzed according to their localization within the ventral spinal cord. Interestingly, the greatest differences were observed in the most ventrally-located interneurons. C_LIO_LIWe conclude that inhibitory interneurons show presymptomatic changes that may contribute to excitatory / inhibitory imbalance in ALS. C_LI

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Cavarsan, C. F., Steele, P. R., McCane, L. M., LaPre, K. J., Puritz, A. C., Katenka, N., Quinlan, K. A.. 2020-10-21. Inhibitory interneurons show early dysfunction in a SOD1 mouse model of ALS. https://doi.org/10.1101/2020.10.21.348359

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