Year: 2018
Type: dissertation
Abstract: Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of the motor system, typically affecting individuals over 60 years of age (Eisen et al. 1993; Brettschneider, Kurent, and Ludolph 2013). It results from motor neuron degeneration in the cortex and spinal cord and is characterized by catastrophic muscle weakness and atrophy that eventually spreads across the body as it progresses into later stages (Kiernan et al. 2011). Without any effective treatments available, ALS is 100% fatal with a median survival of 3 years following the onset of physiological symptoms (Talbot 2009, 2014). Recent studies on cortical dysfunction in ALS have reported anomalies in inhibitory synaptic transmission; however, little is known regarding the role of inhibition in ALS. Sufficient GABAergic inhibitory neurotransmission is not only critical for maintaining a balance between excitation and inhibition, but it is also capable of providing protective effects from excitatory motor neurons in the cortex (Bae et al. 2013). Thus, it is critical to understand how inhibition is affected in ALS and whether the inhibitory circuit can be manipulated to alter the outcome of the disease. The main objective of my PhD project was to determine if parvalbumin-positive (PV+) interneurons in layer 5 (L5) of the primary motor cortex (M1) regulate the pyramidal cell hyperexcitability in the SOD1G93A mouse model of ALS, which has been tightly linked to excitotoxic cell death (Foran and Trotti 2009; Bae et al. 2013). Additionally, using newly developed chemogenetic tools, I aimed to increase PV+-interneuron activity with the goal of reducing pyramidal cell hyperexcitability and delay the onset of ALS-associated symptoms. The principle novel discoveries from my thesis research are: (i) PV+ interneurons are hypoactive in the pre-symptomatic SOD1G93A mouse model of ALS; (ii) increasing PV+ interneuron-mediated inhibition onto L5-M1 pyramidal cells not only rescues M1 pyramidal cell hyperexcitability, it also delays the onset of ALS-associated motor deficits, preserves cortical neuronal populations, and significantly increases the lifespan of SOD1G93A mice; and (iii) tissues from the motor cortex of post-mortem SOD1-ALS patients and SOD1G93A mice show a marked decrease in key inhibitory proteins known to regulate inhibitory function.
Source: TSpace (University of Toronto)
Author: C. Sahara Khademullah
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3093335830