Fig. 9

Schematic diagram showing that FKBP51 mediates inflammation-associated stress adaptation. The scheme illustrates the underlying mechanism of FKBP51-mediated stress adaptation after systemic inflammation. (1) In the inflammation-induced stress model, peripheral LPS stimulation causes activation of the GR signaling that upregulates FKBP51 as well as neuroinflammation, accompanied with upregulation of GAD65 for GABA synthesis, and suppression of c-Fos-indicated neuronal activity, in the ventral hippocampal CA1 subregion; whereas both GAD65 and neuronal activity were reduced in dorsal CA1. The mice under this condition appear to be resilient to inflammatory stress. (2) Although FKBP51 deficiency attenuates the LPS-induced GR expression and proinflammatory cytokines in the hippocampus, such deficiency results in the development of inflammation-induced anxiety, likely via blocking the GAD65 upregulation to de-suppress the neuronal activity in the ventral CA1. In contrast, FKBP51 deficiency does not block the LPS-induced suppression of GAD65 and neuronal activity in dorsal CA1. (3) GC-induced HPA axis hyperactivity does not increase GAD65 expression, thus resulting in the development of anxiety. Fkbp5 deficiency exerted an anxiolytic effect by regulating GR sensitivity in GC-induced stress. Taken together, FKBP51 modulates stress-induced anxiety in various stressors, and plays a critical role in stress adaptation and GABAergic neurotransmission after inflammation in the ventral hippocampus. (↑: increased, ↓: decreased, -: unchanged)