Investigating the role of histone deacetylase HDAC4 in long-term memory formation : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Genetics at Massey University, Manawatu, New Zealand
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Date
2016
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Massey University
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Abstract
Epigenetic mechanisms are emerging as master regulators of cognitive abilities such
as learning and memory. It has been previously shown that the histone deacetylase
HDAC4 plays a critical role in memory formation in both mammals and insects although
the specific mechanisms through which it acts have not yet been elucidated. HDAC4
undergoes nucleocytoplasmic shuttling and, in neurons, it is largely cytoplasmic implying
it may play both nuclear and non-nuclear functions. To identify upstream regulators and
downstream targets of HDAC4, a genetic interaction screen was performed in the fruit fly
Drosophila melanogaster, a powerful model system to study the genetic mechanisms of
neurological disease. Twenty-nine genes were found to interact with HDAC4 suggesting
they are part of the same molecular pathway. Functional network analysis revealed that
many of the genes could be grouped into three biological categories comprising
transcriptional factors, SUMOylation machinery enzymes and cytoskeletal
regulators/interactors. Within the latter, Ankyrin2 was selected for further analysis as it is
implicated in synaptic stability and in human intellectual disability. In addition HDAC4
harbours a conserved ankyrin binding domain. Immunohistochemical analyses showed
widespread distribution of Ankyrin2 throughout the adult brain and coincident
distribution with HDAC4 was observed in the axons of the mushroom body, a key
structure for memory formation in flies. Both HDAC4 and Ankyrin2 were also found to
regulate mushroom body development. RNAi-mediated depletion of Ankyrin2 in the adult
brain impaired long-term memory in the courtship suppression assay, a model of
associative memory and preliminary evidence of a physical association between HDAC4
and Ankyrin2 was also demonstrated. The genes identified in the screen provide new
avenues for investigation of the mechanisms through which HDAC4 regulates memory
formation and preliminary analyses suggest that interaction with the cytoskeletal adaptor
Ankyrin2 may involve remodelling of the actin/spectrin cytoskeleton, phenomenon that
underlies memory related processes like synaptic plasticity and neuronal excitability.
Description
Listed in 2017 Dean's List of Exceptional Theses
Keywords
Histone deacetylase, Long-term memory, Genetic aspects, Research Subject Categories::NATURAL SCIENCES::Biology::Cell and molecular biology::Genetics, Dean's List of Exceptional Theses