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 CB receptors are key determinants of object recognition memory by determining the availability of D-serine at hippocampal synapses. Mutant mice lacking CB receptors from astroglial cells (GFAP-CB-KO) displayed impaired object recognition memory and decreased in vivo and in vitro long-term potentiation (LTP) at CA3-CA1 hippocampal synapses. Activation of CB receptors increased intracellular astroglial Ca levels and extracellular levels of D-serine in hippocampal slices. Accordingly, GFAP-CB-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-CB-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.

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By priming brain circuits, associations between low-salience stimuli often guide future behavioral choices through a process known as mediated or inferred learning. However, the precise neurobiological mechanisms of these incidental associations are largely unknown. Using sensory preconditioning procedures, we show that type 1 cannabinoid receptors (CBR) in hippocampal GABAergic neurons are necessary and sufficient for mediated but not direct learning. Deletion and re-expression of CBR in hippocampal GABAergic neurons abolishes and rescues mediated learning, respectively. Interestingly, paired presentations of low-salience sensory cues induce a specific protein synthesis-dependent enhancement of hippocampal CBR expression and facilitate long-term synaptic plasticity at inhibitory synapses. CBR blockade or chemogenetic manipulations of hippocampal GABAergic neurons upon preconditioning affect incidental associations, as revealed by impaired mediated learning. Thus, CBR-dependent control of inhibitory hippocampal neurotransmission mediates incidental associations, allowing future associative inference, a fundamental process for everyday life, which is altered in major neuropsychiatric diseases. VIDEO ABSTRACT.

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A complex array of different inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically impacts on memory processes is scantly known. We found that a small subclass of type-1 cannabinoid receptor (CB 1 )-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D 1 receptor signaling to GABAergic transmission.Mice lacking CB 1 in D 1 -positive cells (D 1 -CB 1 -KO) displayed impaired long-term, but not short-term, object recognition memory. Re-expression of CB 1 in hippocampal, but not striatal, D 1 -positive cells rescued this memory impairment.Learning induced a facilitation of in vivo hippocampal long-term potentiation (LTP), which was abolished in mutant mice. Chemogenetic and pharmacological experiments revealed that both CB 1 -mediated memory and associated LTP facilitation involves the local control of GABAergic inhibition in a D 1 -dependent manner.This study reveals that CB 1 -/D 1 -expressing interneurons shape hippocampal circuits to sustain recognition memory, thereby identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral and cognitive outcomes.

Summary A complex array of inhibitory interneurons tightly controls hippocampal activity, but how such diversity specifically affects memory processes is not well understood. We find that a small subclass of type 1 cannabinoid receptor (CB 1 R)-expressing hippocampal interneurons determines episodic-like memory consolidation by linking dopamine D 1 receptor (D 1 R) signaling to GABAergic transmission. Mice lacking CB 1 Rs in D 1 -positive cells (D 1 - CB 1 -KO) display impairment in long-term, but not short-term, novel object recognition memory (NOR). Re-expression of CB 1 Rs in hippocampal D 1 R-positive cells rescues this NOR deficit. Learning induces an enhancement of in vivo hippocampal long-term potentiation (LTP), which is absent in mutant mice. CB 1 R-mediated NOR and the associated LTP facilitation involve local control of GABAergic inhibition in a D 1 -dependent manner. This study reveals that hippocampal CB 1 R-/D 1 R-expressing interneurons control NOR memory, identifying a mechanism linking the diversity of hippocampal interneurons to specific behavioral outcomes.

The idea that the effects of drugs largely depend on subcellular target location is emerging as a novel predictive factor of their beneficial or adverse outcomes. G protein-coupled type-1 cannabinoid receptors (CB 1 ) are regulators of several brain functions as well as the main targets of cannabinoid-based medicines.Besides their classical location at plasma membranes, CB 1 receptors are present at different locations within cells, including in association to mitochondrial membranes (mtCB 1 ). Here we report the generation and characterization of a mutant mouse line, which lack mtCB 1 receptors.

The novel object recognition (NOR) task is a behavioral test commonly used to evaluate episodic-like declarative memory and it relies on the innate tendency of rodents to explore novelty. Here we present a maze used to evaluate NOR memory in mice that reduces the time of the assay while improving reliability of the measurements by increasing the exploratory behavior. This memory test, being performed in a two-arms maze, is suitable for several strains of mice (including inbreed and outbreed) and does not require extended training sessions allowing an accurate temporal assessment of memory formation. This particular maze increases the mouse exploration time and reduces variability compared to other arenas used before to assess NOR. As both long-and short-term NOR memory can be easily and accurately quantified using this paradigm, this improved methodology can be easily applied to study pharmacological, genetic or age-related modulation of cognitive function.