Gliotransmission: Beyond Black-and-White

Gliotransmission in context. A simplified schematic of our current view of bidirectional information exchange between neurons and astrocytes via vesicular release of glutamate or d-serine. The cascade begins by (1) synapse activation of the astrocyte (a, b), producing Ca²⁺ elevations (b, c) (e.g., via astrocytic GPCRs; d). These Ca²⁺ transients may rely (2) on IP3 receptors on the ER or on other still not well-defined Ca²⁺ sources, and lead to the release of (3) glutamate (e) or (4) d-serine (f) from the astrocyte, ultimately producing presynaptic (h) or postsynaptic (i) modulatory effects at glutamatergic synapses (g). For clarity, omitted are many other confirmed gliotransmitters (e.g., ATP, lactate, taurine), release mechanisms (e.g., channel mediated and pump release), synaptic effects, and astrocytic signaling receptors and calcium sources (e.g., GPCRs: mGluR5, mGluR3, GABA_B, adrenergic α1, CB1, D1/D2; sources: TRPA1, GLT-1/NCX, P2X) discussed in the text and elsewhere. a, Astrocytes interact with a large number of neuronal synapses located within their domains. A subset of the perforant path axons is transiently labeled with tdTomato, whereas the astrocytes are visualized by expression of eGFP under GFAP promoter (G. Carriero, A.V., unpublished observations). b, Minimal electrical stimulation causes confined local calcium elevations both in a targeted axon and in adjacent astrocytic structures, mostly gliapil (axons: jRCaMP1a; astrocytes: GCaMP6f). Modified with permission from Bindocci et al. (2017). c, Astrocytes show large levels of heterogeneous, spatially disconnected local Ca²⁺ activity in basal condition, particularly at the cell peripheries, in fine processes and gliapil. Shown is a 1 s snapshot of the Ca²⁺ activity (fire) in a GCaMP6f-expressing astrocyte monitored three-dimensionally. The astrocytic core structure, excluding the gliapil, is visualized by uptake of SR101 dye (blue). Modified with permission from Bindocci et al. (2017). d, Astrocytes express metabotropic receptors, including Gq-coupled receptors, which are among those responsible for Ca²⁺ transients. Such receptors often display heterogeneous cell distribution. An example is shown of P2RY1 staining (green) along an astrocytic process (red) in adult hippocampal tissue. Modified with permission from Di Castro et al. (2011). e, Astrocytes were also shown to express vesicular glutamate transporters needed for loading glutamate into exocytotic vesicles. Here single-cell RT-PCR data from astrocytes patched in the adult hippocampus. Modified with permission from Bezzi et al. (2004). f, Complementary immunogold EM evidence, showing the presence of both l-glutamate and d-serine particles in astrocytic synaptic-like microvesicle vesicles, apparently in different vesicle pools. Shown is an example of double-immunostaning for d-serine (small gold particles) and VGLUT1 (large gold particles). Scale bars: 100 and 50 nm in insets. Modified with permission from Bergersen et al. (2012). g, An example of EM staining showing the presence of astrocytic synaptic-like microvesicles directly opposed to putative presynaptic NMDARs. Gold particles represent GluN2b staining. Arrowheads indicate docked synaptic-like microvesicles. The receptors appear to be clustered in presynaptic terminal locations far away from the synaptic cleft and in direct vicinity of the astrocytic structures. Scale bars, 100 nm. Modified with permission from Jourdain et al. (2007). h, i, Synaptic consequences of gliotransmitter release. h, Electrical stimulation of astrocytes causes a transient increase in mEPSC frequency recorded in a nearby dentate gyrus granule cell. This increase is abolished by infusing the astrocyte with a tenatus toxin light chain (TeNT_LC) that disrupts vesicular fusion by cleaving VAMP2 and VAMP3 SNAREs. Modified with permission from Jourdain et al. (2007). This response is mimicked by local P2Y1 receptor activation, blocked by astrocytic Ca²⁺ chelation, and modulated by changing glutamate uptake capacity with TBOA (Jourdain et al., 2007; Di Castro et al., 2011; Santello et al., 2011). i, Astrocytic Ca²⁺ chelation with EGTA-Ca²⁺ clamp solution in the patch pipette blocks hippocampal LTP in the nearby CA3-CA1 synapses, by preventing release of d-serine. Supplementing the slice with exogenous d-serine in the bath solution fully restores LTP. Adapted with permission from Henneberger et al. (2010). LTP was suppressed also when d-serine synthesis was blocked via infusion of the serine racemase inhibitor HOAsp into the astrocyte or when exocytosis was blocked by perfusing the astrocyte with TeNT_LC (Henneberger et al., 2010).