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Genetics and epigenetics of memory functions : from nematodes to human health and disease

Vukojević, Vanja. Genetics and epigenetics of memory functions : from nematodes to human health and disease. 2012, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10182

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Abstract

Identifying the molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Synapses are highly specialized intercellular junctions specialized for transmission of signals between neuron and its target cells. One of the most profound characteristics of synapses is the extraordinary degree of morphological and functional plasticity under basal conditions and also in response to neuronal activity. Synaptic plasticity is a long studied mechanism that is thought to be in the center of memory formation and maintenance. The significance of synapse morphological dynamics for the synaptic plasticity and therefore memory still remains unclear. Taken the advantages of the nematode C. elegans, we investigated α-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory or motor deficits. We showed that α-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1 controlled the storage of memories presumably through actin capping activity in a splice form and tissue specific manner. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for α-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory over distinct species may be helpful in the development of novel strategies to treat memory-related diseases.
In contrast to a relatively deep understanding of how memories are formed, is our limited understanding of how these same memories are maintained. Epigenetic modifications of DNA could be crucial for understanding the molecular basis of complex phenotypes. In the second project we tried to underpin the link between traumatic memories and posttraumatic stress disorder (PTSD) in genocide survivors and DNA methylation. Stress induces a complex set of mechanisms that affect the entire organism. The primary function of those changes is to prepare the organism for the direct consequences of stressful events and to ensure a quick return to homeostasis. Additionally, stress is triggering long-term adaptive responses, which result in enhanced memory of stressful events. Failing to recover from the initial response and to keep the adaptive biological alterations under control leads to impaired homeostasis, results in disorders like PTSD. One of the critical symptoms is loss of the auto-regulation of the stress-induced alterations in HPA (hypothalamic-pituitary- adrenal axis) signaling and increased inhibition of the HPA axis. These changes are maintained over a long period of time, although the underlying mechanisms remain unclear. We investigated epigenetic alterations of the glucocorticoid receptor (GR) gene promoter in saliva samples from survivors of the Rwandan genocide. We found a strong, negative correlation of PTSD symptoms like intrusions, avoidance, and PTSD diagnosis with DNA methylation of the GR gene promoter in genocide survivors. Furthermore, the epigenetic changes were specific to the NGFI transcriptional factor-binding site of the GR promoter and also correlate with GR gene expression. Additionally, we detected a significant negative correlation of LINE-1 element methylation with PTSD risk and avoidance symptoms. Together, our data suggests that epigenetic alterations of glucocorticoid receptor gene and genome-wide in LINE-1 elements could be important for pathophysiology of PTSD and may offer new targets for PTSD diagnosis and treatment. This study also suggests an intriguing possibility of using peripheral tissues for finding epigenetic signatures of some life experiences and complex memory processes. Finally, we took one-step ‘’back’’ to the context of the genomic DNA sequence. This revealed the association of genetic variation in the de-novo DNA methyltransferase 3B gene (DNMT3B) with PTSD symptom clusters and risk. Thus, our study suggests a possible mechanism that loops genetic variation and epigenetic mechanisms as driving forces of the phenotypic plasticity, with development, adaptation and disease. But, instead of revealing a simple predictive code that is shared by many genes, in-depth observation of epigenomic patterns highlights the unique complexity of each transcriptional unit and its associated transcriptional regulatory machinery.
Advisors:Reichert, Heinrich
Committee Members:Papassotiropoulos, Andreas
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Molecular Zoology (Reichert)
Item Type:Thesis
Thesis no:10182
Bibsysno:Link to catalogue
Number of Pages:100 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:51
Deposited On:22 Jan 2013 14:48

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