Abstract:
Synaptic plasticity is critical to learning and memory. However, the exact mechanism by which it is regulated remains unclear. A great deal of effort has been placed into understanding how plasticity works in health and in disease, in the hope of finding a novel therapeutic avenue for neurological disorders. The focus of this thesis is on Histone Deacetylase 4 (HDAC4), an epigenetic molecule thought to be responsible for regulating growth and plasticity in neurons. Past studies have shown that the subcellular localisation of HDAC4 in either the nucleus or the cytoplasm regulates certain cellular functions. Recently, evidence has been building to support the idea that HDAC4 subcellular localisation regulates synaptic plasticity in neurons. To test this, compartment-restricted mutant forms of HDAC4 were packaged into AAV9 viral vectors for delivery into the rat hippocampus. microRNA designed to knock down endogenous rat HDAC4 were also packaged. Bilateral infusions into the dorsal hippocampi were then done using stereotaxic surgery. Animals were then subjected to a battery of behavioural tests after which, brain tissue was collected for immunohistochemical analysis. Behavioural analysis suggests a deficit in location memory and an enhancement of neutral memory in animals that were injected with shuttling-restricted forms of HDAC4. Subsequent immunohistochemical analysis also revealed a possible toxic effect of either HDAC4 knock-down, microRNA, or enhanced green fluorescent protein. This study suggests that the shuttling activity, rather than subcellular localisation of HDAC4, is a regulatory mechanism for learning and memory. Future work should involve replicating the behavioural study, as well as further characterising the toxic effect of AAV9-mediated HDAC4 knockdown and the rescue pathway from HDAC4 overexpression.
