The Role of Synaptic Inhibition in the Primary Motor Cortex of an ALS Mouse Model

Amyotrophic Lateral Sclerosis (ALS) is a fatal disease resulting from the degeneration of motor neurons in the cortex and spinal cord. ALS is the most common neurodegenerative disorder of the motor system and involves progressive muscle weakness and atrophy. Cortical hyperexcitability is a hallmark feature of ALS, and recent studies report reductions in synaptic inhibition in the primary motor cortex (M1) presymptomatically. Rescuing interneuron-mediated inhibition is a promising strategy for reducing hyperexcitability and slowing the onset of ALS. This study aimed to determine whether chemogenetic or pharmacological tools could decrease pyramidal neuron hyperexcitability in Layer 5 of the M1 (L5-M1) in the SOD1G93A ALS mouse model. The principle novel findings of my work are: (i) increasing GABAergic interneuron-mediated inhibition onto L5-M1 pyramidal neurons rescues hyperexcitability of M1 pyramidal neurons and (ii) riluzole reduces hyperexcitability and affects intrinsic membrane properties of M1 pyramidal neurons.M.Sc