Synaptic Integration of Adult-Born Hippocampal Neurons Is Locally Controlled by Astrocytes

Abstract

Adult neurogenesis is regulated by the neurogenic niche, through mechanisms that remain poorly defined. Here, we investigated whether niche-constituting astrocytes influence the maturation of adult-born hippocampal neurons using two independent transgenic approaches to block vesicular release from astrocytes. In these models, adult-born neurons but not mature neurons showed reduced glutamatergic synaptic input and dendritic spine density that was accompanied with lower functional integration and cell survival. By taking advantage of the mosaic expression of transgenes in astrocytes, we found that spine density was reduced exclusively in segments intersecting blocked astrocytes, revealing an extrinsic, local control of spine formation. Defects in NMDA receptor (NMDAR)-mediated synaptic transmission and dendrite maturation were partially restored by exogenous D-serine, whose extracellular level was decreased in transgenic models. Together, these results reveal a critical role for adult astrocytes in local dendritic spine maturation, which is necessary for the NMDAR-dependent functional integration of newborn neurons.

Human-specific features of spatial gene expression and regulation in eight brain regions

“…Both neurons and astrocytes, as well as their interactions, were implicated in learning and memory processes localized in the hippocampus (Henneberger et al 2010;Suzuki et al 2011;Ota et al 2013;Hassanpoor et al 2014;Tadi et al 2015;Gao et al 2016;Pabst et al 2016). Astrocytes were further shown to contribute to the integration of adult-born neurons in the hippocampus, although adult hippocampal neurogenesis in humans remains controversial (Krzisch et al 2015;Sultan et al 2015;Sorrells et al 2018). Moreover, the involvement of hippocampal astrocytes and astrocyte-neuron interactions in Huntington's disease, major depressive disorder, and schizophrenia have been reported (Kolomeets and Uranova 2010;Cobb et al 2016;L'Episcopo et al 2016).…”

The Rise and Fall of the d -Serine-Mediated Gliotransmission Hypothesis

“…A number of studies using different chemical and genetic manipulations of astrocytes in brain slices proposed that D-serine is a gliotransmitter [11, 42, 43]. However, the methodology and selectivity of the astrocytic perturbations used in these studies have been questioned [19, 20, 44], and recent data demonstrating that deletion of the neuronal, but not astrocytic SR impairs synaptic plasticity contradict their findings (Figure 3) [13].…”

Cell Biology of Astrocyte-Synapse Interactions

“…The timeline of astrocyte generation, differentiation and maturation differs between different brain regions; however, astrocyte birth and development usually happens after the main periods of neurogenesis and neuronal migration are completed in the mammalian brain (Miller and Gauthier, 2007). An important exception to this occurs within the neurogenic regions of the adult brain, such as the dentate gyrus of the hippocampus or the subventricular region of the cortex, in which resident astrocytes are thought to provide signals that participate in the generation of new neurons and their integration into existing circuits (Gonçalves et al, 2016; Krzisch et al, 2015; Sultan et al, 2015). …”