Increase in Ia Afferent Synaptic Excitation of SOD1 G93A Mouse Motoneurons by 2‐Week Anodal Trans‐Spinal Direct Current Stimulation Does Not Ameliorate the Cellular Burden of the Disease

An imbalance between cells' intrinsic excitability and synaptic excitation levels underlies the spinal motoneuron (MN) pathophysiology in Amyotrophic Lateral Sclerosis. Recently, a transient restoration of the deficient Ia synaptic excitation of spinal MNs in the presymptomatic SOD1 G93A mice was achieved by applying a single trans-spinal direct current stimulation (tsDCS) session. Here we investigate whether two-week repeated tsDCS applied to presymptomatic SOD1 G93A animals can permanently alter spinal MN synaptic excitation levels and in this way affect intracellular metabolic pathways and cellular burden of the disease. Anodal, cathodal, or sham polarization of 100 μA was applied to P30-P35 SOD1 G93A male mice, and passive membrane properties and Ia excitatory post-synaptic potential (EPSP) characteristics were investigated by intracellular recordings of spinal MNs in vivo. A second cohort of animals was used to test the impact of our intervention on Ia synapse morphology, intracellular metabolic pathways activity, and disease markers. Anodal tsDCS evoked a strong increase in maximal Ia EPSPs amplitudes, coupled with a significant upregulation of GluR4 subunits of AMPA receptors at the Ia synapse. The cathodal polarization failed to induce any alteration to Ia synapse morphology, but increased the input resistance of MNs. However, changes in MN electrophysiological profile and Ia synapse morphology did not translate into alterations of intracellular molecular pathways activity and did not decrease the cellular burden of the disease. Our results indicate a strong polarity-dependent plasticity of spinal MNs in SOD1 G93A mice in response to tsDCS, which however does not alleviate disease burden.