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Investigating the role of pro-inflammatory signalling in the mechanisms of synapse weakening


About This PhD Project

Project Description

The changing of synaptic connections between neurons is integral to normal physiological function in the brain, and is central to the ebb and flow of dynamic synaptic connectivity. However, mounting evidence suggests that ‘synapse weakening processes’ can be aberrantly upregulated in certain disease states, and this might underpin the loss of synapses in particular pathologies. Indeed, soluble oligomeric forms of amyloid-β protein (Aβ) are neurotoxic and lead to neurodegeneration in Alzheimer’s disease (AD), and we have previously shown that Aβ regulates a key synapse-weakening pathway convergent on the activation of caspase-3 and GSK-3β (Jo et al., 2011). The upstream catalyzing factors behind these effects, however, remain to be fully understood.
Neuroinflammatory signaling is activated in response to a noxious stimulus, and usually serves to restore homeostasis and induce the repair of the damaged area. However, emerging evidence suggests that chronic activation of pro-inflammatory signaling can cause synapse elimination (Rao et al., 2012), and in particular the C1q component of the complement system is thought to play an important role (Stephan et al., 2012). These effects could be critically important in chronic and progressive disease, which can result in the sustained activation of these inflammatory responses (Frank-Cannon et al., 2009). However, the precise mechanisms of how pro-inflammatory signaling might link with synapse weakening are not known. This project therefore aims to investigate the role of neuroinflammatory signaling, particularly the complement system, in the induction and expression of the synapse weakening signaling pathway, both under physiological and pathological (e.g., Aβ-driven synaptotoxicity) conditions.
This project will take a multidisciplinary approach, bringing together brain-slice electrophysiology and in vitro molecular biology analysis techniques. The student will learn a range of investigative techniques, including extracellular field potential recording, whole-cell patch clamp recording, organotypic brain slice culture and protein assays.

When applying please select ’Neuroscience PhD’ within the Faculty of Health Sciences.

References

Jo et al. (2011). Nat. Neurosci. 14, 545-7.
Frank-Cannon et al. (2009). Mol. Neurodegen. 4, 47.
Stephen et al. (2012). Annu. Rev. Neurosci. 35, 369-89.
Rao et al. (2012). Neurochem. Res. 37, 903-10.

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