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J Psychiatr Res. 2016 Jan;72:43-50. doi: 10.1016/j.jpsychires.2015.10.015. Epub 2015 Oct 26.

Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: A potential mediator between mitochondria and immune-activation.

Author information

1
Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: helenakim0913@gmail.com.
2
Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada; Center for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada. Electronic address: ana.andreazza@utoronto.ca.
3
Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: nikaelmi@gmail.com.
4
Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: wenjun.chen@mail.utoronto.ca.
5
Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada; Center for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada. Electronic address: ltrevor.young@utoronto.ca.

Abstract

Mitochondrial complex I dysfunction, oxidative stress and immune-activation are consistently reported in bipolar disorder (BD). Mitochondrial production of reactive oxygen species was recently linked to activation of an inflammatory redox sensor, the nod-like receptor family pyrin domain-containing 3 (NLRP3). Upon its activation, NLRP3 recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to form the NLRP3-inflammasome, activating IL-1β. This study aimed to examine if immune-activation may be a downstream target of complex I dysfunction through the NLRP3-inflammasome in BD. Post-mortem frontal cortex from patients with BD (N = 9), schizophrenia (N = 10), and non-psychiatric controls (N = 9) were donated from the Harvard Brain Tissue Resource Center. Levels of NLRP3, ASC and caspase-1 were measured by western blotting, ELISA and Luminex. While we found no effects of age, sex or post-mortem delay, lower levels of complex I (F2,25 = 3.46, p < 0.05) and NDUFS7, a subunit of complex I (F2,25 = 4.13, p < 0.05), were found in patients with BD. Mitochondrial NLRP3 (F2,25 = 3.86, p < 0.05) and ASC (F2,25 = 4.61, p < 0.05) levels were higher in patients with BD. However, levels of caspase 1 (F2,25 = 4.13, p < 0.05 for both), IL-1β (F2,25 = 7.05, p < 0.01), IL-6 (F2,25 = 5.48, p < 0.05), TNFα (F2,25 = 7.14, p < 0.01) and IL-10 (F2,25 = 5.02, p < 0.05) were increased in both BD and schizophrenia. These findings suggest that immune-activation in the frontal cortex may occur both in patients with BD and schizophrenia, while complex I dysfunction and NLRP3-inflammasome activation may be more specific to BD.

KEYWORDS:

Bipolar disorder; Complex I; Frontal cortex; NLRP3; Oxidative stress; Post-mortem brain

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