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Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Biochemistry

Collaborative Specialization

Developmental Biology

Supervisor

Berube, Nathalie G.

Abstract

Mutations in ATRX, a Snf2-type chromatin remodeler, frequently lead to intellectual disability. However, the function of ATRX within the brain in cognition and synaptic transmission are incompletely understood. The aim of this study was to investigate the role of ATRX in the adult mouse brain. While complete loss of ATRX in the embryonic mouse brain results in perinatal lethality, mosaic expression of ATRX stunted growth and perturbed circulating IGF-1 levels. Mosaic expression of ATRX also impaired adult cognition, specifically recognition memory and spatial learning and memory. However, there were confounding factors that led me to a new model in which I deleted the gene in postnatal mouse glutamatergic neurons. Magnetic resonance imaging of these mice revealed increased hippocampal CA1 and CA3 layers, and behaviour analysis indicated deficiencies in hippocampal-dependent learning and memory in the contextual fear task, Morris water maze, and paired-associate learning task. These behavioural abnormalities were not present in the female counterparts. Transmission electron microscopy of male hippocampal CA1 synapses revealed decreased number of total and docked vesicles and increased cleft width and post-synaptic density size. Hippocampal RNA-sequencing followed by sex-interaction analysis of male and female knockout transcripts highlighted potential impairments in the synaptic vesicle cycle. miR-137, a known regulator of presynaptic vesicle cycle and plasticity, was upregulated in the male knockout hippocampi but downregulated in the female knockouts. These results demonstrate sexually-dimorphic regulation of miR-137 and learning and memory by ATRX in forebrain glutamatergic neurons, indicating potential miRNA-targeting therapies for cognitive disorders by ATRX mutations.

Summary for Lay Audience

The ATRX gene is required for the ATRX protein which modifies how the genetic material, DNA, is packaged and regulated in brain cells. When there is no ATRX present in the cell, there is deregulation of many different genes. Mutations during development that decrease the function of ATRX result in an intellectual disability disorder known as ATR-X syndrome. This syndrome is characterized by intellectual disability, developmental delay, abnormalities in facial structure, and small brain size. Therefore, ATRX is important in our nervous system and loss is directly related to many mental health disorders. My project focuses on the role of ATRX in learning and memory. I hypothesize that ATRX plays a very important role in the control of genes required for learning and memory by altering expression of genes involved in this process. In order to look at the effects that ATRX has on epigenetics in the adult brain, I generated two mouse models that deletes ATRX in the brain – one in the whole brain, and one in areas important for learning and memory. These mice underwent various behaviour tests to determine if they were able to learn and remember different tasks. I found that the mutant mice were unable to form two distinct types of memories: spatial memories and fear memories. I also found that loss of ATRX causes abnormal brain size in areas required for learning and memory. Additionally, ATRX may be required to regulate a particular microRNA, which in turn can regulate many different genes involved in proper neuron function. In summary, my work demonstrates a role for ATRX in learning and memory, thereby providing another link between chromatin remodeling proteins and cognition.

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

Supplementary Table 1 (List of transcripts).xlsx (83 kB)
Supplementary Table 1

Available for download on Tuesday, June 01, 2021

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