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Nuclear calcium regulates dendrite maintenance, memory formation and fear extinction

Hemstedt, Thekla Joana

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Abstract

Throughout our entire life, memory is central to our ability to carry out everyday tasks. Therefore, diseases that affect cognition have severe consequences, that influence patients' daily lives. However, not only do deficits in forming or recalling memories impact peoples' lives but also the inability to forget traumatic events or fear towards specific stimuli, such as with post-traumatic stress disorder (PTSD), anxiety disorders and phobias. Hence, it is essential to understand the cellular and molecular mechanisms in order to help people with any of these disorders. In the first study of this thesis, I investigated if nuclear calcium, which is known to control cAMP response element binding protein (CREB)/CREB binding protein (CBP)-mediated transcription is required for the formation of memory. Indeed, I found that inhibition of hippocampal nuclear calcium impairs memory formation in two hippocampus-dependent tasks. I further investigated the possible mechanisms that contribute to these deficits and found that dysregulation of nuclear calcium leads to alterations in dendritic morphology. I was able to rescue these morphological alterations via overexpression of the vascular endothelial growth factor D (VEGFD). VEGFD is regulated by nuclear calcium under basal conditions and is known to be important for the maintenance of dendritic morphology. Additionally, I could show that overexpression of VEGFD rescued memory deficits caused by nuclear calcium inhibition, probably due to the restoration of the dendritic architecture. In the second study, we aimed to investigate whether DNA methyltransferases (DNMTs) are required for memory formation. We found that DNMT3a2 is regulated by nuclear calcium and is induced upon neuronal activity. Additionally, we were able to show that the level of DNMT3a2 determines memory performance in mice. Downregulation of DNMT3a2 caused memory deficits and, in addition, a decrease in DNMT3a2 expression was associated with age-dependent memory decline. Further, restoring the level of DNMT3a2 in aged mice rescued memory impairments. In addition, we showed that DNMT3a2 expression correlates with global methylation levels, and we were able to identify two of the target genes of DNMT3a2, namely, activity-regulated cytoskeleton-associated protein (ARC) and brain-derived neurotrophic factor (BDNF). In the third part of this thesis, I studied if nuclear calcium is also required for fear memory extinction, which is routinely used as a model of PTSD. It is widely accepted that during fear extinction a new memory is built up that inhibits the previous, acquired memory. Though it is known that memory formation and fear extinction share common mechanisms, studies investigating the role of transcription in fear extinction are partly controversial. Here, I have shown that nuclear calcium is involved in fear extinction, pointing to a requirement of gene transcription. As I have shown in the first study of this thesis, nuclear calcium, which maintains the dendritic architecture primarily via alterations in the dendritic tree, probably also contributes to fear memory extinction. In summary, I have shown in this thesis that nuclear calcium mediates two forms of cognition, memory formation and fear extinction. I provide evidence that nuclear calcium-regulated VEGFD maintains the dendritic structure, which is important for the permissiveness of the neuron to process information required for long-term adaptations. Additionally, nuclear calcium regulates DNMT3a2, and we show that the level of DNMT3a2 has an impact on memory formation. Overexpression of DNMT3a2 restored the level of DNMT3a2 in aged mice and rescued age-dependent memory deficits.

Item Type: Dissertation
Supervisor: Bading, Prof. Dr. Hilmar
Date of thesis defense: 24 April 2015
Date Deposited: 30 Jul 2015 07:16
Date: 2016
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
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