Astroglial CB1 Receptors Determine Synaptic D-Serine Availability to Enable Recognition Memory

Abstract

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.

Keywords: D-serine; NMDA receptors; astrocytes; astroglial CB1 receptors; hippocampus; in vitro LTP; in vivo LTP; memory; object recognition; synapse.