Distinct endocannabinoids specifically signal to astrocytes or neurons in the adult mouse hippocampus
Nature Neuroscience. 2025-12-30; 29(2): 445-454
DOI: 10.1038/s41593-025-02148-1
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https://www.bordeaux-neurocampus.fr/12410
1. Nat Neurosci. 2026 Feb;29(2):445-454. doi: 10.1038/s41593-025-02148-1. Epub
2025 Dec 30.
Distinct endocannabinoids specifically signal to astrocytes or neurons in the
adult mouse hippocampus.
Noriega-Prieto JA(#)(1), Falcón-Moya R(#)(1)(2), Noeker JA(1), Cai R(3)(4),
Fundazuri UB(5)(6), Eraso-Pichot A(5)(6), Cai S(3)(4), Guttipatti P(1), Belisle
L(1), Rodríguez-Moreno A(2), van der Stelt M(7), Li Y(3)(4), Cheer JF(8)(9),
Marsicano G(5)(6), Kofuji P(10), Araque A(11).
Author information:
(1)Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
(2)Laboratorio de Neurociencia Celular y Plasticidad, Departamento de
Fisiología, Anatomía y Biología Celular, Universidad Pablo de Olavide, Sevilla,
Spain.
(3)PKU-IDG/McGovern Institute for Brain Research, Beijing, China.
(4)State Key Laboratory of Membrane Biology, Peking University School of Life
Sciences, Beijing, China.
(5)INSERM, U1215 NeuroCentre Magendie, Bordeaux, France.
(6)University of Bordeaux, Bordeaux, France.
(7)Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden
University and Oncode Institute, Leiden, the Netherlands.
(8)Department of Neurobiology, University of Maryland School of Medicine,
Baltimore, MD, USA.
(9)Department of Psychiatry, University of Maryland School of Medicine,
Baltimore, MD, USA.
(10)Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
.
(11)Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA.
.
(#)Contributed equally
The endocannabinoid (eCB) system is involved in many processes in brain
function. eCBs depress synaptic transmission by directly activating presynaptic
CB1 receptors (CB1Rs), and they indirectly potentiate adjacent synapses by
activating astrocytic CB1Rs. In contrast to other neurotransmitter systems, the
brain eCB system involves two endogenous ligands, 2-arachidonoylglycerol (2-AG)
and anandamide (AEA), and the receptor CB1R. The meaning of this particularity
remains unknown. Here we show that 2-AG selectively signals to neurons,
eliciting the depression, which is mediated exclusively by neuronal mechanisms.
By contrast, AEA signals to astrocytes, inducing lateral synaptic potentiation.
Moreover, AEA, but not 2-AG, and astrocyte-mediated signaling are required for
hippocampal spike-timing-dependent long-term potentiation. Hence, while 2-AG
selectively signals to neurons, AEA specifically signals to astrocytes, evoking
contrasting regulatory phenomena of synaptic transmission and plasticity. These
results reveal distinct cell-type-specific signaling pathways that involve
unique eCBs selectively signaling to either neurons or astrocytes.
© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.
DOI: 10.1038/s41593-025-02148-1
PMID: 41469443 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: The authors declare no
competing interests.