Regulation of Memory by the Actin-Binding Protein Cofilin

The concept of disability is complex, constantly evolving and hard for many to understand. Disabilities, including those that are non-apparent such as some neurodevelopmental disorders, are often associated with negative preconceptions. Though neurodevelopmental disorders can affect language, speech, learning, memory, motor skills and other functions, individuals with these disorders can still lead meaningful lives. While many developmental disorders are associated with impaired learning and memory, different stages and types of memory can be affected. These impairments are often correlated with altered neuronal structure or function. Therefore, understanding the molecular mechanisms is important to better understand neurodevelopmental disorders. One process that is important for neuronal development is remodeling of the actin cytoskeleton. This remodeling is regulated by the actin binding protein cofilin, but its role in learning and memory remains unclear. Physiologically relevant manipulations of cofilin activity in vivo provide new opportunities for examining its function in learning and memory. Therefore, in this thesis, I examined three objectives to determine how cofilin overexpression in vivo affects the actin cytoskeleton and memory. I first characterized two novel transgenic mouse models that allow for either overexpression of wild-type or constitutively inactive forms of cofilin with spatial and temporal regulation. Expression of transgenic cofilin was robustly localized in excitatory neurons and processes in both mouse models. However, rod-like structures thought to be cofilin-actin aggregates were observed in cofilin overexpressing mice. I then showed that cofilin overexpression impaired short-term social novelty recognition, which was rescued by reversible transgene expression. Though it is unclear if the impairment was due to an underlying deficit in recognizing novelty. In contrast, some mice expressing constitutively inactive cofilin exhibited a possible immobility phenotype. However, further testing is required to determine the reproducibility of these impairments. Finally, cofilin-overexpressing zebrafish showed transgene expression throughout the nervous system, with rod-like structures in neuronal processes similar to those in mice with no effect on locomotion. Together, these results suggest that the novel transgenic cofilin models provide valuable tools for future research on the roles of cofilin and actin regulation in a variety of neuronal processes.

Department dc:contributor.department

Physiology

Year dc:date.issued

2023

Author dc:creator

• Merovitch, Neil H

Advisors dc:contributor.advisor

• Lefebvre, Julie L
• Jia, Zhengping

• Actin
• ADF
• Cofilin
• Zebrafish

Statement dc:rights

• Attribution-NonCommercial 4.0 International

Licence dc:rights.uri

• http://creativecommons.org/licenses/by-nc/4.0/

Handle dc:identifier.uri

http://hdl.handle.net/1807/128158

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/128158