Bidirectional communication between neurons and astrocytes shapes synaptic plasticity and behavior. D-serine is a necessary co-agonist of synaptic N-methyl-D-aspartate receptors (NMDARs), but the physiological factors regulating its impact on memory processes are scantly known. We show that astroglial CB1 receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB1 receptors from astroglial cells (GFAP-CB1-KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses. Activation of CB1 receptors increased intracellular astroglial Ca2+ levels and extracellular levels of D-serine in hippocampal slices. Accordingly, GFAP-CB1-KO displayed lower occupancy of the co-agonist binding site of synaptic hippocampal NMDARs. Finally, elevation of D-serine levels fully rescued LTP and memory impairments of GFAP-CB1-KO mice. These data reveal a novel mechanism of in vivo astroglial control of memory and synaptic plasticity via the D-serine-dependent control of NMDARs. Robin et al. show that astroglial CB1 receptors in the hippocampus regulate D-serine supply to NMDA receptors, a process necessary for LTP induction and object recognition memory.
Bibliographical noteFunding Information:
We thank Nathalie Aubailly, Magali Dubuc, and all the personnel of the Animal Facility of the NeuroCentre Magendie for mouse care. We thank Delphine Gonzales and all the personnel of the Genotyping Facility of the NeuroCentre Magendie. We thank the Histology and Biochemistry platforms of the NeuroCentre Magendie for help in the experiments. We thank also C. De Rijck (Vrije Universiteit Brussel) for help with experiments, and all the members of Marsicano’s lab for useful discussions. This work was supported by INSERM (G.M. and S.H.R.O.), CNRS (S.H.R.O. and A.P.), EU–Fp7 ( PAINCAGE, HEALTH-603191 , G.M.), European Research Council ( Endofood, ERC-2010-StG-260515 and CannaPreg, ERC-2014-PoC-640923 , G.M.), Fondation pour la Recherche Médicale ( DRM20101220445 and DPP20151033974 , G.M.; FDT20160435664 , J.F.O.d.C.; DEQ 20130326519 , S.H.R.O.; FDT20150532252 , V.C.L.), Human Frontiers Science Program ( RGP0036//2014 , G.M. and A.A.), Region Aquitaine (G.M.), Agence Nationale de la Recherche ( ANR Blanc NeuroNutriSens ANR-13-BSV4-0006 , G.M., and BRAIN ANR-10-LABX-0043 , G.M., S.H.R.O., L.M.R., Animal Facility, Genotyping Facility, Histology Platform, and Biochemistry Platform), Fyssen Foundation and CONACyT (E.S.-G.), EMBO and FRM post-doc fellowships (L.B.), and French Ministry of Higher Education and Research (L.M.R. and V.C.L.).
- NMDA receptors
- astroglial CB1 receptors
- in vitro LTP
- in vivo LTP
- object recognition