Anodal tsDCS restores the structure and function of the disrupted proprioceptive Ia synapses on spinal motoneurons in the SOD1 G93A mouse model of ALS

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Abstract
An imbalance between cells’ intrinsic excitability and synaptic excitation levels is the basis of spinal motoneuron (MN) pathophysiology in Amyotrophic Lateral Sclerosis. Recently, a restoration of the deficient Ia synaptic excitation of spinal MNs was achieved by applying acute trans-spinal direct current stimulation (tsDCS) to presymptomatic SOD1 G93A mice. Here we investigate whether two-week repeated tsDCS applied to presymptomatic SOD1 animals can provoke spinal MN neuroplasticity and reduce the disease burden. Anodal, cathodal or sham polarisation of 100 µA was applied to P30-P35 SOD1 G93A mice; 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 polarized animals was used to test the impact of our intervention on Ia synapse morphology, MN intracellular metabolic pathways activity, and disease markers. Anodal tsDCS evoked a strong increase in maximal Ia EPSPs, coupled with a significant upregulation of vesicular glutamate transporter levels and GlurR4 subunits of AMPA receptors at the Ia synapse. On the other hand, cathodal polarisation failed to induce any significant alteration to Ia synapse morphology but did increase both peak and plateau input resistance and recovered the abnormal paired-pulse ratio. Unexpectedly, the changes in MN electrophysiological profile and Ia synapse morphology did not translate into alterations of intracellular pathways ctivity and did not decrease the disease burden. Altogether our results indicate a strong polarity-dependent plasticity of spinal MNs in SOD1 G93A mice in response to tsDCS, which nevertheless appears insufficient to alter disease dynamics. Highlights: 14-days of trans-spinal direct current stimulation (tsDCS) alters the electrophysiological properties and morphology of Ia proprioceptive synapses on spinal MNs in SOD1 G93A mouse model of ALS Anodal (depolarising) tsDCS increases MN synaptic excitation and restores the postsynaptic elements of the Ia synapse Cathodal (hyperpolarising) tsDCS increases MN input resistance but does not impact Ia synapse morphology Both anodal and cathodal tsDCS fail to significantly modify the cellular burden of the disease

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