Posted by Leanne Kodsmann on
New research validates the PAI-1 knockout mouse as a preclinical genetic model of human depression, while demonstrating that this knockout also serves as a model for antidepressant resistance. Not only that, but this new research shows PAI-1 is involved in depression separately from the tPA-BDNF axis. As a result, PAI-1 could be a novel target for developing new treatments for major depressive disorder.
If research dollars were allocated according to the extent of human distress, major depressive disorder (MDD) would likely rise near the top of the list.
Why is this?
MDD impacts as many as 350 million people globally, making it one of the most common disorders in the world and a leading cause of disability. In fact, the World Health Organization predicts that depression will become the largest contributor to worldwide disease by 2030.
Although MDD is a common illness, it often goes undiagnosed. Even when diagnosed and treated, as many as 40% of patients will prove resistant to currently available treatments like SSRIs (selective serotonin reuptake inhibitors), the most commonly-prescribed antidepressants.
To date, the genetic and environmental factors that lead to major depressive disorder remain largely unknown, but that is changing as new research continues to look at the pathogenesis of depression.
The Monoamine Hypothesis of Depression
The most common hypothesis of major depressive disorder is known as the monoamine hypothesis. This hypothesis predicts that in individuals with MDD, their serotonin, norepinephrine, and/or dopamine levels are depleted and this deficiency functions as the pathophysiologic basis of depression.
This is the prevailing model for depression, and the hypothesis upon which most antidepressants have been developed and evaluated. However, this hypothesis does not explain the latency of antidepressant response, as response to treatment is rarely immediate and typically requires weeks of medication administration before symptoms improve. Because of this, additional hypotheses are contributing to promising therapeutic approaches for treating major depressive disorder.
The Neurotrophic Hypothesis of Depression
The neurotrophic hypothesis of depression proposes that a key factor in both the development of major depressive disorder and a patient's response to treatment with antidepressants is neuronal plasticity, referring to the brain's ability to adapt to changes. This adaptability includes important functions like compensating for injury or disease.
Brain-Derived Neurotrophic Factor, or BDNF, is a key component of neuronal plasticity. BDNF provides trophic support to cell structure and function, and mediates the stimulation of neurogenesis by antidepressants. Antidepressants can recover neurons within weeks, thus explaining the latency in response to antidepressant treatment.
PAI-1 as a Biomarker for Major Depressive Disorder
Research has repeatedly demonstrated that PAI-1 levels are elevated in human patients with MDD, but while PAI-1 has been identified as an interesting potential biomarker related to depression, the exact impact of PAI-1 in the pathogenesis of MDD has remained an open question.
One idea is that, as a primary inhibitor of Tissue Plasminogen Activator (tPA), perhaps PAI-1 plays a role in depression through inhibiting tPA as part of the tPA-BDNF Axis in the following way:
- Under normal conditions, Mature BDNF (mBDNF), a critical part of maintaining neuronal plasticity, is created when its precursor (proBDNF) is cleaved by the tPA-Plasminogen system.
- Because PAI-1 traditionally functions as a primary inhibitor of tPA, it has been suggested that PAI-1 could play a role in major depressive disorder through inhibiting tPA.
- This tPA inhibition may in turn inhibit the cleaving of proBDNF to create mBDNF, leading to decreased neuronal plasticity and an increased risk of developing MDD.
Putting PAI-1 to the Test
This idea of PAI-1 contributing to depression through tPA inhibition was quickly gaining ground and being mentioned as a possibility in a growing body of published research. Still, the impact of PAI-1 on MDD remained only a suggestion and had not been directly tested, so a team of researchers got to work devising a novel study to investigate exactly whether and how PAI-1 contributes to MDD.
Using both PAI-1 knockout mice and tPA knockout mice, the research team compared the knockout mice to their wild type littermates with specific focus on the mechanisms connecting PAI-1 and MDD. Depressive symptoms were assessed using a variety of behavioral tests, and the researchers investigated both prevailing mechanistic hypotheses (monoaminergic and neurotrophic) to see if and how PAI-1 contributed to each.
Their results were published in October 2019, in a paper titled Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments, available in the journal Acta Neuropathologica Communications. This research is notable, especially regarding three findings in particular:
The PAI-1 knockout mouse functions as genetic model of depression.
The PAI-1 knockout mouse model displayed a depressive phenotype, and this phenotype was found to be associated with changes in the monoamine levels related to MDD.
The PAI-1 knockout mouse functions as a genetic model of antidepressant resistance.
The PAI-1 knockout mouse model was found to be SSRI-resistant, functioning as a preclinical model of antidepressant treatment resistance. Knowing that as many as 40% of MDD patients can be resistant to treatment, this finding could be of great benefit to future research into new therapeutic approaches.
The involvement of PAI-1 in depression is independent of the tPA-BDNF axis.
Contrary to the suggestion that the role of PAI-1 in MDD could be a result of tPA inhibition, the research found that the role of PAI-1 is independent of the tPA-BDNF axis as measured in two distinct ways. First, the research did not show variation in active tPA or mBDNF levels between the PAI-1 knockout mice and wild type controls. Second, when evaluating tPA knockout mice, the research found that although these mice lack all tPA protein expression they did not display any apathetic and/or anhedonic depressive behaviors and therefore did not function as a model for MDD.
Where Research is Headed Next
Known genetic variants of the SERPINE1 gene (the gene related to PAI-1 protein production) have been observed in humans to relate to MDD, and this recent research strengthens this connection. Not only that, but the PAI-1 knockout mouse has been shown to serve as a model for SSRI resistance, and directly demonstrates that PAI-1 involvement in MDD is independent of tPA and BDNF. Because of this, PAI-1 could prove to be a groundbreaking therapeutic target for future treatment of MDD, but there is still a lot of research that needs to happen before that is possible.
Future studies will likely look to identify the biological mechanisms involved, especially as related to the signaling cascades downstream of PAI-1 and how it plays into the development of MDD. This is an area of research that is rapidly evolving, and it will undoubtedly be exciting to see what new advancements are discovered along the way.
References and Further Reading:
- Ledford, H. (2014). Medical research: If depression were cancer. Nature, 515(7526), 182–184. doi:10.1038/515182a
- WHO, 2008. The Global Burden of Disease: 2004 Update. WHO.
- Pang, P. T. (2004). Cleavage of proBDNF by tPA/Plasmin Is Essential for Long-Term Hippocampal Plasticity. Science, 306(5695), 487–491. doi:10.1126/science.1100135
- Willner, P., Scheel-Krüger, J., & Belzung, C. (2013). The neurobiology of depression and antidepressant action. Neuroscience & Biobehavioral Reviews, 37(10), 2331–2371. doi:10.1016/j.neubiorev.2012.12.007
- Boku, S., Nakagawa, S., Toda, H., & Hishimoto, A. (2017). Neural basis of major depressive disorder: Beyond monoamine hypothesis. Psychiatry and Clinical Neurosciences, 72(1), 3–12. doi:10.1111/pcn.12604
- Jiang, H., Li, X., Chen, S., Lu, N., Yue, Y., Liang, J., … Yuan, Y. (2016). Plasminogen Activator Inhibitor-1 in depression: Results from Animal and Clinical Studies. Scientific Reports, 6(1). doi:10.1038/srep30464
- Party, H., Dujarrier, C., Hébert, M., Lenoir, S., Martinez de Lizarrondo, S., Delépée, R., … Agin, V. (2019). Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments. Acta Neuropathologica Communications, 7(1). doi:10.1186/s40478-019-0807-2