The contribution of spinal inhibitory circuits to aberrant excitability in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease targeting motoneurons, leading to paresis and death.

Changes in spinal microcircuits have been suggested to be part of an early homeostatic response to preserve motor output, possibly involving substantial alterations at the level of premotor synapses.

Supported by solid preliminary data, I hypothesize that changes in these circuits precede motoneuron degeneration, and thus propose to address these aims: (1) define early disruptions in connectivity to motoneurons in ALS and (2) determine the genetic profile of these abnormalities.

I will characterize well-known spinal synaptic pathways such as Ia excitation, disynaptic reciprocal inhibition and pre-synaptic inhibition in wildtype mice and 2 different models of ALS (SOD1G93A and TDP-43-A315T).

I will do this both in vitro, by using a novel isolated mature mouse spinal cord preparation, and in vivo by performing intracellular recordings of motoneurons and EMG recordings with chronically implanted multielectrode arrays.

These experiments will be complemented with transcriptomic analysis using single-cell patch seq and laser capture microscopy to reveal if changes in specific spinal microcircuits are accompanied by changes in expression profile of motoneurons and interneurons. This project will reveal if early degeneration in ALS results in generalized circuit impairment.