Knockdown of the glucocorticoid receptor alters functional integration of newborn neurons in the adult hippocampus and impairs fear-motivated behavior

Abstract

Glucocorticoids (GCs) secreted after stress reduce adult hippocampal neurogenesis, a process that has been implicated in cognitive aspects of psychopathology, amongst others. Yet, the exact role of the GC receptor (GR), a key mediator of GC action, in regulating adult neurogenesis is largely unknown. Here, we show that GR knockdown, selectively in newborn cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration. Strikingly, GR knockdown induced ectopic positioning of a subset of the new granule cells, altered their dendritic complexity and increased their number of mature dendritic spines and mossy fiber boutons. Consistent with the increase in synaptic contacts, cells with GR knockdown exhibit increased basal excitability parallel to impaired contextual freezing during fear conditioning. Together, our data demonstrate a key role for the GR in newborn hippocampal cells in mediating their synaptic connectivity and structural as well as functional integration into mature hippocampal circuits involved in fear memory consolidation.

Glucocorticoid‐mediated modulation of morphological changes associated with aging in microglia

“…Therefore, we hypothesized that reducing microglial sensitivity to GC in old mice should further aggravate age‐related microglial amoebification. To test this hypothesis, GR expression was knocked down in 20‐month‐old mice (Figure 2g) as previously described (Fitzsimons et al., 2013; Schouten et al., 2015). Of note, limitations of this siRNA‐mediated knockdown approach include the intrahippocampal delivery itself that might induce alterations in the tissue for which we controlled with noncoding siRNA and the lack of cell‐type specificity.…”

“…Of note, limitations of this siRNA‐mediated knockdown approach include the intrahippocampal delivery itself that might induce alterations in the tissue for which we controlled with noncoding siRNA and the lack of cell‐type specificity. The latter might be accompanied by neuronal GR knockdown impacting spine density (Fitzsimons et al., 2013), possibly contributing to changes in microglial morphology. Nevertheless, nuclear GR protein levels in CD11b+/Iba1+ cells were reduced to ~10%, 3 days post‐injection (dpi; Figure 2h–i), which was accompanied by a decrease in hippocampal CD11b coverage (Figure 2j,k) and microglial complexity (Figure 2l–n).…”

Fine processes of Nestin-GFP–positive radial glia-like stem cells in the adult dentate gyrus ensheathe local synapses and vasculature

“…VEGF is one of these factors (83), and can stimulate neurogenesis (84)(85)(86) and reversibly modulate neuronal plasticity (87). Other blood-derived factors capable of affecting neurogenesis are glucocorticoids, which are necessary for the regulation of neuronal differentiation and migration (88). Adult neuronal stem cells themselves were recently shown to release a substantial VEGF-A signal (89), a signal that is received by other neuronal stem cells, via the VEGF receptor (VEGFR)2, and is necessary for maintenance of the RGL stem cell population.…”

Regulation of Adult Neurogenesis and Plasticity by (Early) Stress, Glucocorticoids, and Inflammation

“…Although more information has become available on its molecular control Anacker et al 2013;Fitzsimons et al 2013;Miller et al 2013), the precise mechanism by which GCs decrease the number of new neurons remains unknown, but N-methyl-D-aspartate (NMDA) receptors, GRs and MRs, are present on the new cells, albeit in different ratios over time, and they likely act in concert to mediate effects of stress on the neurogenic process (Montaron et al 2003;Herbert 2004, 2005). Notably, GR knockdown, selectively in cells of the hippocampal neurogenic niche, accelerates their neuronal differentiation and migration.…”