Postgraduate research opportunities Does proteinase-activated receptor 2 (PAR2) activation play a key role in depression?

Four proteinase-activated receptors (PARs1-4) are G protein-coupled receptors (GPCR) that have a novel activation mechanism and have been implicated in various inflammation-related diseases in both the periphery and central nervous system (CNS)¹.  We have previously investigated the role of one PAR subtype, PAR2, in CNS function revealing that its activation modulates neuronal excitability², is neuroprotective³ and plays a role in sickness behaviour⁴.  We have extended these findings and now have novel data indicating that PAR2 activation leads to depression-like behaviour in mice.  Importantly, this behavioural phenotype is associated with inflammatory changes observed in patients suffering from major depressive disorder (MDD) and treatment-resistant depression (TRD).  Given our preliminary data, we hypothesise that PAR2 activation induces depression-like behaviour via inflammatory mechanisms.  Thus the aim of this project is to test this hypothesis by examining the following research questions:

1. What inflammatory cell types are involved in PAR2-induced depression-like behaviour?
2. What cellular and signalling pathway(s) underlie PAR2-induced behavioural changes?
3. Does peripheral inflammation plays a role in the centrally-mediated behavioural changes?

Answer to these questions will identify a potential novel therapeutic target for those patients who are resistant to current therapies for MDD.

Techniques used

Behavioural testing of depression-like behaviour, immunohistochemistry, innate and adaptive immune cell assays using FACS analysis, cytokine assays using ELISA.

Further information

1: Bushell TJ, Cunningham MR, McIntosh KA, Moudio S, Plevin R. Protease-Activated Receptor 2: Are Common Functions in Glial and Immune Cells Linked to Inflammation-Related CNS Disorders? Curr Drug Targets. 2016;17(16):1861-1870.

2: Gan J, Greenwood SM, Cobb SR, Bushell TJ. Indirect modulation of neuronal excitability and synaptic transmission in the hippocampus by activation of proteinase-activated receptor-2. Br J Pharmacol. 2011 163:984-94.

3: Greenwood SM, Bushell TJ. Astrocytic activation and an inhibition of MAP kinases are required for proteinase-activated receptor-2-mediated protection from neurotoxicity. J Neurochem. 2010 113:1471-80.

4: Abulkassim R, Brett R, MacKenzie SM, Bushell TJ. Proteinase-activated receptor 2 is involved in the behavioural changes associated with sickness behaviour. J Neuroimmunol. 2016 295-296:139-47.