Astrocytes constitute a major proportion of cells in the hippocampal neurogenic niche, where they regulate neurogenesis through the release of soluble factors. However, the role of astrocytes in the synaptogenesis and integration of adult-born neurons into existing circuits is unknown. In this study, Sultan et al. show that astrocytes in the adult mouse neurogenic niche release D-serine, which is required for normal dendritic maturation, spine formation and functional integration of adult-born neurons.
The authors used two types of conditional transgenic mice in which exocytosis from hippocampal astrocytes could be selectively disrupted. In the first type, tamoxifen administration could induce the expression of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-cleaving toxin hippocampal astrocytes, whereas in the second type, a dominant-negative variant of the SNARE domain of synaptobrevin 2 (dnSNARE mice) was controlled by doxycycline administration. In both types of mice, transgene expression was determined by green fluorescent protein expression, allowing hippocampal astrocytes in which transgene expression had been induced to be distinguished from unaffected cells.
Hippocampal astrocyte processes are non-overlapping, whereas the dendritic trees of adult-born neurons extend into multiple astrocytic territories, thus allowing the authors to determine the effect of inhibition of vesicle fusion in transgenic astrocytes compared with unaffected astrocytes on dendrites of the same newborn neurons.
Interestingly, the authors found that dendrites in territories where astrocytic vesicle fusion had been inhibited had lower levels of synaptogenesis than dendrites that extended outside of these territories. This suggests that astrocytes locally regulate spine maturation. Furthermore, the survival of adult-born neurons was reduced by around 40% when astrocytic vesicle release was inhibited.
excitatory synapse formation requires astrocytic vesicle release
Next, the authors determined whether alterations in dendritic and spine maturation also resulted in functional implications for excitatory synaptic transmission. Whole-cell patch-clamp recording of adult-born neurons in dnSNARE mice exhibited marked reductions in AMPA receptor (AMPAR)-mediated and NMDA receptor (NMDAR)-mediated currents. These neurons also exhibited lower spine density, fewer mature synapses and shorter dendrites than neurons in wild-type mice, suggesting that excitatory synapse formation requires astrocytic vesicle release.
As adult-born neurons mature, they become silent, and the unsilencing of such neurons requires GABA receptor-mediated depolarization combined with synaptic activation, which involves NMDAR activation and the induction of synaptic AMPAR expression. The authors found that extracellular D-serine (an NMDAR co-agonist) was decreased in dnSNARE mice compared with controls. Moreover, exogenous application of D-serine in acute brain slices from dnSNARE mice rescued the reduction in NMDAR-mediated currents that was observed in adult-born neurons, and chronic administration of D-serine increased dendritic length, arborization and spine formation to levels that were similar to those seen in wild-type animals.
Overall, these data indicate that D-serine, released from hippocampal astrocytes, regulates the survival, maturation and functional integration of adult-born neurons into existing neural circuits.
Sultan, S. et al. Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 88, 957–972 (2015)
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Lewis, S. Astrocytic parenting?. Nat Rev Neurosci 17, 4 (2016). https://doi.org/10.1038/nrn.2015.14