Activation of local inhibitory circuits in the dentate gyrus by adult‐born neurons

Abstract

Robust incorporation of new principal cells into pre-existing circuitry in the adult mammalian brain is unique to the hippocampal dentate gyrus (DG). We asked if adult-born granule cells (GCs) might act to regulate processing within the DG by modulating the substantially more abundant mature GCs. Optogenetic stimulation of a cohort of young adult-born GCs (0 to 7 weeks post-mitosis) revealed that these cells activate local GABAergic interneurons to evoke strong inhibitory input to mature GCs. Natural manipulation of neurogenesis by aging – to decrease it – and housing in an enriched environment – to increase it – strongly affected the levels of inhibition. We also demonstrated that elevating activity in adult-born GCs in awake behaving animals reduced the overall number of mature GCs activated by exploration. These data suggest that inhibitory modulation of mature GCs may be an important function of adult-born hippocampal neurons.

RB controls growth, survival, and neuronal migration in human cerebral organoids

“…Supporting these results, RB1-KO organoids showed an increase in the expression of CCNA2, which regulates the G1-to Sphase transition (Macleod et al, 1996). What is surprising is that there was also increased cell death in RB1-KO organoids compared with wild type at 28 DIV, possibly due to an increase of the proapoptotic gene BAX (Drew et al, 2016). In line with our results, it has been described that loss of RB in mice promotes apoptosis in the developing and adult brain (Macleod et al, 1996;Vandenbosch et al, 2016;Yu et al, 2012).…”

Adult hippocampal neurogenesis and cognitive flexibility — linking memory and mood

“…Of note, 5HT1ARs are G i protein-coupled receptors that silence neuronal activity by opening G protein-coupled inward-rectifying potassium (GIRK) channels 159 . Therefore, it is possible that inhibiting dentate gyrus function may elicit antidepressant or anxiolytic effects, which is consistent with the proposed inhibitory role of young adult-born granule cells 69 (BOX 1). This assertion is also supported by a study showing that blocking GABA type A receptors in the ventral, but not in the dorsal, dentate prevents the anxiolytic effects of exercise 56 .…”

“…For example, neurogenesis ablation only increases immediate early gene expression in the dentate gyrus during neurogenesis-dependent conflict situations 67 . Accordingly, optogenetic activation of adult-born neurons decreases dentate gyrus activity in conditions of novelty and anxiety, whereas the activation of a similar number of mature granule cells has no effect on the activity of the remaining mature cells 69 . However, in vitro slice electrophysiology has shown that, under baseline conditions, mature (8-week-old) adult-born neurons are stronger inhibitors of the dentate gyrus than young (4-week-old) neurons 70 .…”

“…For example, the ablation of neurogenesis by X-ray irradiation increases dentate gyrus gamma burst amplitude and increases the number of active mature granule cells during reversal learning tasks 66,67 . Conversely, increasing neurogenesis reduces dentate gyrus excitability 68 , and optogenetic stimulation of adult-born neurons reduces mature granule cell activity 69 .…”

“…At the microcircuit level, presynaptic terminals onto hilar interneurons develop at ~4 weeks of age and recruit feedback inhibition onto mature granule neurons 40,54 (see the figure, part a ). Accordingly, increasing neurogenesis in mice through environmental enrichment or transgenic strategies inhibits mature granule cells and reduces the overall excitability of the DG 68,69 . In line with this requirement for neurogenesis in DG inhibition, optogenetic stimulation of young neurons activates GABAergic interneurons in the hilus, and these interneurons in turn inhibit the dense population of mature cells in vivo and in vitro 69,70 .…”