Losing Connection: Developmental Stress and Synaptic Loss in Caenorhabditis elegans

Synapses are connections that propagate neural transmissions within the nervous system and throughout an organism. They begin to form during development and are in a continuous state of formation and elimination as animals age. A deficiency in formation or improper elimination of synapses could be a causative factor in the early stages of neurological disorders and disease such the most common form of dementia, Alzheimer’s disease (AD). It is widely recognized that organismal stress can contribute to less desirable outcomes in AD and other related disorders. Using the nematode Caenorhabditis elegans as a model, we examine how organismal stress affects developmental and age-related synaptic formation and elimination and explore the potential pathways involved. In chapter III we demonstrate that stress from either genetic, proteotoxic, pathogenic, or chemical exposure results in the generation of fewer net synapses. We observed a synergistic developmental loss in animals experiencing combined stress from proteotoxic and pathogenic stress. Together, these results suggest multiple mechanisms of response contributing to fewer developmental synapses in animals responding to organismal stress. Due to the natural decline in neural function, all organisms undergo a normal progressive synaptic loss with aging. A heightened amount of stress experienced during development can affect the trajectory of age-related disease onset and outcomes. In Chapter IV our results demonstrate that persistent or acute stress during development impacts synaptogenesis and can induce a degenerative synaptic phenotype that persists through aging. We also show that a combination of stress can induce an attenuation of synaptic loss early in adulthood. This mitigation is suggestive of multiple stress response pathways that induces a transient positive outcome in relation to synaptic degeneration. In addition, these results indicate that this altered synaptic trajectory is stimulated early in adulthood. In chapter V we investigate the mechanism behind the temporary delay in synaptic degeneration observed in animals experiencing combined proteotoxic and-pathogenic stress. Hypothesizing that an adult program of gene expression changes as a result of organismal stress response pathways are responsible for the visible increase in synapses, we performed a transcriptomic analysis on early adult (day 2) worms. A comparative analysis revealed that animals experiencing attenuation of loss had an increased expression of genes comparable to C. elegans overexpressing the UPRmt inducing histone demethylase jmjd-3.1. We show that expression of jmjd-3.1 is not necessary for synaptic development but is necessary for protection against stress-related synaptic loss from ROS and combined stress in aging animals. We also demonstrated that transgenic overexpression of jmjd-3.1 is sufficient to induce synaptogenesis during normal and stressed conditions with the exception of pathogen exposure. We conclude that in stressed C. elegans there are multiple mechanisms of stress response including the UPRmt that work in parallel. Some of these include pathways that are antagonistic to the protective response induced by jmjd-3.1 expression. A balance of synaptic molecule related gene expression changes is essential to maintain proper synaptic formation and maintenance during development and throughout aging. In Chapter VI we explore the changes in gene expression seen in animals that upregulate jmjd-3.1 on day two as a response to combined stress. We show that upregulated genes are associated with synaptic development, function, and neurotransmitter release. In combination our data reveals a previously unidentified function for jmjd-3.1 in a stress-induced adult program of synaptic formation and maintenance. In conclusion our results give evidence that some age-associated neurodegenerative disorders might be initiated by occurrences earlier in life than previously thought. These occurrences induce multiple response pathways whose coordination and overlap can either result in enhanced negative outcomes or attenuation of decline. These adult programs of histone modifications and response pathways induction may provide insight into potential mechanisms to delay or reverse disease associated synaptic loss in AD and other neurodegenerative disorders.

Grantor dc:publisher

University of Kansas

Year dc:date.issued

2025

Author dc:creator

• Amrein, Jennifer K.

Advisor dc:contributor.advisor

• Ackley, Brian D.

• Neurosciences
• Developmental biology
• Aging
• Alzheimer's disease
• genetics
• mitochondria
• stress response
• synapses
• tau

Statement dc:rights

• This item is protected by copyright and unless otherwise specified the copyright of this thesis/dissertation is held by the author.

Language dc:language.iso

en

Dc Identifier Other

https://www.proquest.com/LegacyDocView/DISSNUM/31938957

OAI identifier oai:identifier

oai:kuscholarworks.ku.edu:1808/38168