Project Summary/Abstract
Failure to form and store long-term memories is a feature of cognitive decline in aging and neurodegeneration.
Experts predict that the prevalence of cognitive impairment, ranging from mild to severe dementia, will increase
alongside the rapidly growing U.S. population of older adults aged 65 and older, creating new challenges to
provide resources and care for older adults. There is a need to understand the epigenetic and molecular
mechanisms of memory formation in the aging brain to develop early intervention strategies and preserve
cognitive function in old age. As observed in our lab and others, histone deacetylase 3 (HDAC3) is a powerful
epigenetic regulator of memory formation and synaptic plasticity. However, mechanisms regulating HDAC3 in
the aging brain with regards to memory remain undefined. Emerging data suggesting that HDAC3 may be
regulated in cancer cells by upstream kinases and phosphatases led me to hypothesize that the phosphorylation
state of HDAC3 determines the ability of HDAC3 to regulate memory formation and synaptic plasticity.
Furthermore, that the mechanism of HDAC3 phosphorylation becomes dysregulated during memory
consolidation in the aging brain, contributing to age-related memory impairments. Preliminary data in this
proposal reveals that baseline levels of phospho-HDAC3 are reduced in the hippocampus of aging mice (18-mo)
compared to young adult mice (3-mo). Additionally, I developed HDAC3 mutant viral constructs to test the
function of phosphorylated HDAC3 (phospho-mimic) and de-phosphorylated HDAC3 (phospho-null) in memory
formation and synaptic plasticity in the young adult and aging brain. Preliminary results demonstrate that viral
expression of the HDAC3 phospho-mimic impairs memory formation and synaptic plasticity in young adult mice.
However, expression of the HDAC3 phospho-null in aging mice ameliorated age-related impairments in memory
formation and synaptic plasticity. Together, these findings suggest that HDAC3 phosphorylation is a mechanism
that can dynamically regulate long-term memory and synaptic function. Therefore, this proposal will focus on
continuing to investigate the epigenetic regulation of HDAC3 phosphorylation on memory formation in the adult
and aging male and female brain. Specific aims within this proposal will determine the following: Aim 1, determine
the role of HDAC3 phosphorylation in the young adult brain; Aim 2, determine the role of HDAC3 phosphorylation
in the aging brain; Aim 3, determine the mechanism by which HDAC3 phosphorylation regulates memory
formation in the young adult and aging brain. Findings from this project will potentially elucidate a novel
mechanism of HDAC3 epigenetic regulation in memory that can have a fundamental impact for all aging
individuals with cognitive impairments. This training fellowship will allow for development of molecular,
physiology and bioinformatics expertise. With the guidance of Dr. Wood and the research and professional
environment at UCI, this fellowship will provide a foundation for successful career as an independent investigator
focused on understanding the epigenetic mechanisms underlying learning and memory in the aging brain.