Investigation into the role of the RNA methyltransferase NSun2 in neuroplasticity regulation

  • Harry George

Student thesis: Doctoral ThesisPhD

Abstract

Disruption of the NSun2 gene in humans is known to cause an intellectual disability syndrome. The clinical presentation of the disorder is similar to Fragile X Syndrome and Tuberous Sclerosis Complex, two diseases which have been strongly associated with deficits in synaptic plasticity formation. The NSun2 protein, which can regulate protein synthesis, is known to locate to the dendrites of neurons, thus raising the possibility that it too may play a role in postsynaptic modulation pathways. Utilising a transgenic NSun2-deficient murine model, this thesis work aimed to investigate whether disruption of NSun2 might lead to relevant synaptic plasticity defects known to be associated with impaired memory and learning. Thus ex-vivo field recordings were obtained from the CA1 hippocampus of NSun2-deficient mice via stimulation of the schaffer collateral pathway. Alongside these experiments, whole cell current-clamp recordings were used to investigate intrinsic properties and plasticity of Cornu Ammonis (CA) 1 pyramidal neurons. The field recordings demonstrated a deficit in N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) and long term depression (LTD) with no deficits observed in metabotropic glutamate receptor (mGluR)-LTD. The current-clamp recordings revealed that NSun2 mutant pyramidal cells fire action potentials at a faster rate and have a faster membrane time constant.

The work presented in this thesis suggest that the key neurological aspects observed in NSun2-deficiency syndromes may be caused by deficits in hippocampal synaptic plasticity mechanisms, with NMDA receptor signalling playing important, likely central, roles.
Date of Award2 Oct 2019
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorRobert Williams (Supervisor) & Shobbir Hussain (Supervisor)

Cite this

Investigation into the role of the RNA methyltransferase NSun2 in neuroplasticity regulation
George, H. (Author). 2 Oct 2019

Student thesis: Doctoral ThesisPhD