FKBP5 modulates the hippocampal connectivity deficits in depression: a study in twins

Abstract

The hippocampus is a key modulator of stress responses underlying depressive behavior. While FKBP5 has been found associated with a large number of stress-related outcomes and hippocampal features, its potential role in modifying the hippocampal communication transfer mechanisms with other brain regions remains largely unexplored. The putative genetic or environmental roots of the association between depression and structural connectivity alterations of the hippocampus were evaluated combining diffusion weighted imaging with both a quantitative genetics approach and molecular information on the rs1360780 single nucleotide polymorphism, in a sample of 54 informative monozygotic twins (27 pairs). Three main results were derived from the present analyses. First, graph-theoretical measures of hippocampal connectivity were altered in depression. Specifically, decreased connectivity strength and increased network centrality of the right hippocampus were found in depressed individuals. Second, these hippocampal alterations are potentially driven by familial factors (genes plus shared environment). Third, there is an additive interaction effect between FKBP5's rs1360780 variant and the graph-theoretical metrics of hippocampal connectivity to influence depression risk. Our data reveals alterations of the communication patterns between the hippocampus and the rest of the brain in depression, effects potentially driven by overall familial factors (genes plus shared twin environment) and modified by the FKBP5 gene.

The FKBP51 Glucocorticoid Receptor Co-Chaperone: Regulation, Function, and Implications in Health and Disease

“…In general, it is currently hypothesized that depressed patients have increased basal FKBP51 levels [ 155 , 183 , 184 ] (although not observed in all populations [ 115 , 185 ]) that may be leading to a GR resistance [ 186 , 187 ]; alternatively, the basal promoter activity may be less relevant than the stress reactivity of the promoter that is shaped by genotype and epigenotype [ 6 ]. Moreover, the FKBP5 genotype has been reported to interact with the MDD diagnosis to predict structural neuroanatomical changes [ 116 , 188 , 189 , 190 ], as well as with prior lifetime trauma and/or stress to increase the risk for depression [ 191 , 192 , 193 , 194 ]. A recent meta-analysis performed with 26,582 subjects has also confirmed a significant association between both rs1360780 and rs3800373 with MDD [ 195 ].…”

Western High-Fat Diet Consumption during Adolescence Increases Susceptibility to Traumatic Stress while Selectively Disrupting Hippocampal and Ventricular Volumes

“…An important modulator of these interactions is FKBP5 (Hoeijmakers et al, 2014; Schmidt et al, 2015), which codes for the FK506-binding protein 51 (FKBP51) and has emerged as a promising drug target for its involvement in numerous neuropsychiatric disorders, including PTSD (Binder et al, 2004, 2008; Binder, 2009; Binder et al, 2010; Lavebratt et al, 2010; Ellsworth et al, 2013; Klengel et al, 2013; Alemany et al, 2016; Stamm et al, 2016; Yehuda et al, 2016). Notably, new studies show a strong relationship between the FKBP5 gene and hippocampal volumes and connectivity (Zobel et al, 2010; Fani et al, 2013; Córdova-Palomera et al, 2016). Thus, FKBP51 may play a role in predisposing the brain to traumatic stress by virtue of regulating the structural integrity of the hippocampus.…”

Research progress in the brain area responsible for depression

“…In recent years, some studies have further conducted controlled experiments and concluded that the correlation between Tardive Depression and hippocampal volume was stronger than that of early-onset depression, and the smaller hippocampus volume is associated with higher levels of cortisol [16]. Besides, stress-related FKBP5 was related to hippocampal characteristics [17]. After analyzing a sample of a certain number of identical twins, it was concluded that the right hippocampus of patients with depression has decreased connection strength and increased network centrality, thereby revealing the manner in which the hippocampus communicates with the rest of the brain in those who are depressed.…”