Coordinate and Region-Specific Roles for Fibroblast Growth Factors 2 and 9 as Molecular Organizers in Major Depression and Animal Models of Affective Disorders.

Abstract

The neurotrophic hypothesis posits that changes in the expression and function of growth factors in the brain underlie the pathophysiology of Major Depressive Disorder (MDD). Previous work implicated the fibroblast growth factor (FGF) system, identifying FGF2 as an endogenous anxiolytic and antidepressant molecule whose expression is downregulated in the depressed brain. Notably, FGF9 showed a diagnosis-specific pattern of expression that was opposite to FGF2. Therefore, we investigated the hypotheses that FGF2 and FGF9 were critical to the regulation of affect and that their expression becomes disrupted in MDD. Because the literature supporting the role of FGF9 in affect regulation was small, we performed exploratory analyses and demonstrated that FGF9 expression is consistently upregulated in the hippocampus (but not the anterior cingulate cortex or dorsolateral prefrontal cortex) of individuals diagnosed with MDD. We also showed that reducing endogenous expression of FGF9 in the dentate gyrus is sufficient to reduce anxiety-like behavior, and hippocampal FGF9 levels differ in an animal model of affective dysregulation. Because they showed opposite effects in MDD and animal models, we hypothesized that FGF2 and FGF9 might act as physiological antagonists to mediate affect. We examined more complex questions regarding FGF2. We used animal models to demonstrate that altered hippocampal FGF2 expression predisposes individuals for affective dysregulation. Because we hypothesized that relative levels of FGF2 and FGF9 might be important to MDD pathophysiology, we examined diagnosis-specific relationships in expression between FGF2, FGF9, and FGF receptors, and we found regional patterns of alteration with MDD. In the anterior cingulate cortex, correlations between FGF family members were lost in MDD, while in the hippocampus, new relationships emerged. These changes were related to alterations in correlated gene expression of transcripts related to fundamental biology and circuit function, supporting the hypothesis that FGF2 and FGF9 may influence affect by acting as molecular organizers whose effects become dysregulated during MDD. Future studies will examine the role of FGF2 and FGF9 in MDD, with a particular emphasis on understanding how neural circuitry is altered at the cellular level.