Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines

Moudio, Serge and Willis, Ashleigh and Pytka, Karolina and Abulkassim, Roua and Brett, Ros R. and Webster, Jack F. and Wozny, Christian and Barbour, Mark and Jiang, Hui-Rong and Watson, David G. and van Kralingen, Josie C. and Mackenzie, Scott M. and Daniels, Michael and McColl, Barry W. and Sossick, Sandra and Nuthall, Hugh N. and Bushell, Trevor J. (2022) Protease-activated receptor 2 activation induces behavioural changes associated with depression-like behaviour through microglial-independent modulation of inflammatory cytokines. Psychopharmacology, 239 (1). pp. 229-242. ISSN 0033-3158 (https://doi.org/10.1007/s00213-021-06040-1)

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Abstract

Rationale: Major depressive disorder (MDD) is a leading cause of disability worldwide but currently prescribed treatments do not adequately ameliorate the disorder in a significant portion of patients. Hence, a better appreciation of its aetiology may lead to the development of novel therapies. Objectives: In the present study, we have built on our previous findings indicating a role for protease-activated receptor-2 (PAR2) in sickness behaviour to determine whether the PAR2 activator, AC264613, induces behavioural changes similar to those observed in depression-like behaviour. Methods: AC264613-induced behavioural changes were examined using the open field test (OFT), sucrose preference test (SPT), elevated plus maze (EPM), and novel object recognition test (NOR). Whole-cell patch clamping was used to investigate the effects of PAR2 activation in the lateral habenula with peripheral and central cytokine levels determined using ELISA and quantitative PCR. Results: Using a blood–brain barrier (BBB) permeable PAR2 activator, we reveal that AC-264613 (AC) injection leads to reduced locomotor activity and sucrose preference in mice but is without effect in anxiety and memory-related tasks. In addition, we show that AC injection leads to elevated blood sera IL-6 levels and altered cytokine mRNA expression within the brain. However, neither microglia nor peripheral lymphocytes are the source of these altered cytokine profiles. Conclusions: These data reveal that PAR2 activation results in behavioural changes often associated with depression-like behaviour and an inflammatory profile that resembles that seen in patients with MDD and therefore PAR2 may be a target for novel antidepressant therapies.

ORCID iDs

Moudio, Serge, Willis, Ashleigh, Pytka, Karolina, Abulkassim, Roua, Brett, Ros R., Webster, Jack F., Wozny, Christian ORCID logoORCID: https://orcid.org/0000-0003-4220-2033, Barbour, Mark, Jiang, Hui-Rong, Watson, David G., van Kralingen, Josie C., Mackenzie, Scott M., Daniels, Michael, McColl, Barry W., Sossick, Sandra, Nuthall, Hugh N. and Bushell, Trevor J. ORCID logoORCID: https://orcid.org/0000-0003-4145-9670;
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