Tiffany C. Ho, Ph.D.
Fellow in Child & Adolescent Depression
Ian H. Gotlib, Ph.D.
Manpreet K. Singh, M.D., M.S.
Understanding the Course of Adolescent Depression: Cytokines, Glutamate, and Glutathione
Inflammatory cytokines play a critical role in normal brain development and function; moreover, they influence neurotransmitter systems, which are responsible for chemical communication between brain cells. In the face of acute stress, cytokines are produced by the immune system to promote adaptive responses. Chronic exposure to elevated levels of cytokines, however, leads to persistently high levels of glutamate, a major excitatory neurotransmitter, in the dorsolateral prefrontal cortex (DLPFC), a key brain region involved in emotion regulation and implicated in Major Depressive Disorder (MDD). The presence of elevated glutamate results in over excitation of neurons and, eventually, cell death. Importantly, glutathione, the body’s primary endogenous antioxidant, is involved in modulating glutamate transmission. While work in adults suggest that MDD is characterized in part by elevated inflammation and DLPFC glutamate, no investigators have tested this model in adolescents with MDD. Therefore, it is unknown whether elevated inflammation and DLPFC glutamate represent biomarkers of MDD or are the consequence of chronic depression. To disentangle these possibilities, it is important to relate inflammation and glutamate levels with the clinical course of adolescents with MDD. To identify developmentally-appropriate intervention targets for this population, it will also be important to assess whether antioxidants involved in glutamate transmission, such as glutathione, mediate inflammation and depression severity to promote recovery from MDD. To test these hypotheses, we propose to relate cytokines assayed from blood, DLPFC glutamate, and DLPFC glutathione levels acquired in 40 adolescents with MDD, and relate these biomarkers with their clinical course.
I am honored to have been selected for this Fellowship by the KTGF and hope that my work will represent the mission of the Foundation to its fullest.