Theses Doctoral

Axon Initial Segment Plasticity in Mouse Models of Amyotrophic Lateral Sclerosis

Smerdon, John W.

Amyotrophic Lateral Sclerosis (ALS) is a debilitating and fatal neurodegenerative disease affecting upper and lower motor neurons. Though studied for over two decades since the first ALS-associated genetic mutation was discovered, researchers have yet to uncover the pathological processes that lead to progressive degeneration of motor neurons in ALS, or to develop effective treatments. One prominent hypothesis proposes that excitotoxicity caused by increased motor neuron firing plays a role in ALS pathogenesis. While prior studies reported increased action potential firing in early postnatal ALS-model motor neurons in vivo, it remains unknown whether the increased activity stems from increased intrinsic excitability of ALS motor neurons or from increased excitatory drive, and whether these changes are transient or persist into adulthood, when ALS symptoms emerge.
In this thesis, I circumvented the difficulties in standard measurement of electrophysiological properties of adult spinal motor neurons in vivo by relying on the visualization of the axon initial segment, a subcellular structure known to undergo compensatory structural changes in response to perturbations in excitatory input. I discovered that cultured motor neurons derived from stem cells of the SOD1G93A mouse model of ALS display shortened axon initial segments and hypoexcitable electrophysiological properties. The shortening of the axon initial segment is compensatory, as ALS motor neurons receive increased numbers of excitatory inputs and manifest increased spontaneous activity. Remarkably, similar shortening of the axon initial segment was detected in early presymptomatic spinal motor neurons in vivo. The shortened axon initial segment persists into the symptomatic stages and is particularly pronounced in motor neurons containing p62 immunoreactive aggregates and neurons exhibiting swollen mitochondria, two signs of stress and neurodegeneration in the disease. Based on these observations I propose that early in the presymptomatic stages of the disease, spinal motor neurons recruit excessive excitatory inputs, resulting in their increased activity that is in part compensated by shortening of the axon initial segment. This state persists and becomes even more pronounced in motor neurons exhibiting biochemical changes preceding neurodegeneration.
While these observations support the potential role for excitotoxic stress in spinal ALS motor neurons, I paradoxically observed the opposite phenotype in ALS-vulnerable cranial motor neurons in the brainstem of the SOD1G93A animals, raising the possibility that the cellular stress that drives the neurodegeneration in ALS is motor neuron subtype specific.


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More About This Work

Academic Units
Cellular Physiology and Biophysics
Thesis Advisors
Wichterle, Hynek
Ph.D., Columbia University
Published Here
January 11, 2019