INTERNEURON TO MOTOR NEURON SYNAPTIC DEFICITS IN MOUSE MODELS OF AMYOTROPHIC LATERAL SCLEROSIS

Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by the degeneration of somatic motor neurons (MNs). As the final output of the brain, MNs directly connect to the muscles, but they are activated by a complex network of excitatory and inhibitory spinal interneurons (INs). Previous research in our lab (1) showed that spinal V1 spinal inhibitory INs, positive for Engrailed 1 (En1) transcription factor (2) are affected in the disease prior to muscle denervation and MN degeneration (1): specifically, they lose their connections to MNs. Inhibitory IN dysfunctions can trigger maladaptive MN hyperexcitability, resulting in increased intracellular Ca2+ levels, oxidative stress, and endoplasmic reticulum stress, extensively reported in ALS (3). However, this loss of synaptic inputs can be caused either by MN- or V1 IN-degenerative mechanisms. Preliminary transcriptomics results from our lab point towards synaptic deficits and SNARE complex alterations in INs as a main feature in the disease; thus, this study assesses Unc13a, Stxbp1 and Snap25 in SOD1G93A, TDP43-NLS and FUSR521C mice (Walker et al 2015) using RNAscope to further understand the IN-MN loss of connectivity. Along with a significant reduction in En1 transcript in V1 INs, we found changes in expression of the presynaptic transcripts that differed between MNs and INs. This indicates major deficits in synaptic transmission paralleled by the motor phenotypes in these models.