Motor System Connectivity Influences in Amyotrophic Lateral Sclerosis

Communication between neurons and muscles occurs at synaptic connections which are often compromised in neuromuscular disease. Multiple hypotheses on where connections breakdown exist for amyotrophic lateral sclerosis (ALS). Do the earliest changes occur at the spinal motor neuron or the cortical level? How do disruptions in axonal transport contribute? Underlying these potential mechanisms is the neural circuitry which ultimately mediates the pathological process. This proposal will unravel the synaptic connections to motor neurons innervating affected muscles and determine how these change in ALS. Our hypothesis is that synaptic inputs to muscles affected in ALS will change with disease progression; these inputs will enable us to predict disease spread through the motor system.

First, we will map the neural circuitry that controls the motor neurons innervating two hindlimb muscles in the mouse using transneuronal viral tracers. Both fast- and slow-twitch muscles will be included to identify muscle fiber/motor neuron-type specific changes. By defining the direct and more elaborate multi-synaptic pathways, we can determine how and when synaptic connections are affected as ALS progresses. We will investigate pre-symptomatic, denervation, symptom onset and end-stage disease phases. The time course of synaptic connectivity changes and transport deficits will be elucidated, providing insights into mechanisms underlying degeneration and leading to targeted therapeutic options.