Study about neural inflammation in mental illness and development of drug screening using in vitro models of disease

Abstract

The current therapeutic drugs for major depression mainly modulate monoaminergic signaling. Since they are not effective for all patients, the development of novel therapeutic target is required. Recently, it has been reported that inflammation-related molecules are increased in the blood from patients with major depression. Therefore, neuroinflammation is a possible cause of these disorders. However, we still do not know whether neuroinflammation induces depression. Since social and environmental stress is a risk factor for mental illnesses, repeated social defeat stress is employed as an animal model of depression. We found that prostaglandin E₂ (PGE₂) suppresses mesocortical dopaminergic pathway to induce behavioral changes and cyclooxygenase-1 (COX-1), a key enzyme for PGE₂ production, is essential for repeated stress-induced PGE₂ production and behavioral changes. Based on the finding that COX-1 is expressed in microglia in the brain, we are wondering if microglia plays an important role in stress-induced behavioral changes. We revealed that Toll-like receptor (TLR) 2 and 4 in prefrontal microglia are crucial for repeated stress-induced behavioral changes. Our results indicate that repeated social defeat stress induces microglial activation through TLR2 and 4, thereby leading to neuronal and behavioral changes through proinflammatory cytokines such as TNFα and IL-1α. These findings revealed the essential role and molecular basis of neuroinflammation. In addition, we developed the drug screening platform which targets neuroinflammation for neurodegenerative disease such as amyotrophic lateral sclerosis. Our findings pave the way for the development of therapeutic drugs for major depression targeting neuroinflammation which causes neurological disorders.