Anatomical characterization of the cannabinoid CB1 receptor in cell‐type–specific mutant mouse rescue models
Open accessAbstract
ABSTRACT Type 1 cannabinoid (CB1) receptors are widely distributed in the brain. Their physiological roles depend on their distribution pattern, which differs remarkably among cell types. Hence, subcellular compartments with little but functionally relevant CB1 receptors can be overlooked, fostering an incomplete mapping. To overcome this, knockin mice with cell‐type–specific rescue of CB1 receptors have emerged as excellent tools for investigating CB1 receptors’ cell‐type–specific localization and sufficient functional role with no bias. However, to know whether these rescue mice maintain endogenous CB1 receptor expression level, detailed anatomical studies are necessary. The subcellular distribution of hippocampal CB1 receptors of rescue mice that express the gene exclusively in dorsal telencephalic glutamatergic neurons (Glu‐CB1‐RS) or GABAergic neurons (GABA‐CB1‐RS) was studied by immunoelectron microscopy. Results were compared with conditional CB1 receptor knockout lines. As expected, CB1 immunoparticles appeared at presynaptic plasmalemma, making asymmetric and symmetric synapses. In the hippocampal CA1 stratum radiatum, the values of the CB1 receptor‐immunopositive excitatory and inhibitory synapses were Glu‐CB1‐RS, 21.89% (glutamatergic terminals); 2.38% (GABAergic terminals); GABA‐CB1‐RS, 1.92% (glutamatergic terminals); 77.92% (GABAergic terminals). The proportion of CB1 receptor‐immunopositive excitatory and inhibitory synapses in the inner one‐third of the dentate molecular layer was Glu‐CB1‐RS, 53.19% (glutamatergic terminals); 2.30% (GABAergic terminals); GABA‐CB1‐RS, 3.19% (glutamatergic terminals); 85.07% (GABAergic terminals). Taken together, Glu‐CB1‐RS and GABA‐CB1‐RS mice show the usual CB1 receptor distribution and expression in hippocampal cell types with specific rescue of the receptor, thus being ideal for in‐depth anatomical and functional investigations of the endocannabinoid system. J. Comp. Neurol. 525:302–318, 2017. © 2016 Wiley Periodicals, Inc.
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Functional expression of TRPV1 may be underestimated if TRPV1 is expressed post- and presynaptically and acts far away from its synthesis sites.
“functional expression may be underestimated if TRPV1 is expressed post and presynaptically (Aguiar et al., 2014) and acts far away from its synthesis sites (Gutierrez-Rodriguez et al., 2016; Ruehle et al., 2013).”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Gutierrez-Rodriguez et al., 2016
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The endocannabinoid system as a target for novel anxiolytic drugs
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“…in dorsal telencephalic glutamatergic neurons (Glu-CB1-RS) or GABAergic neurons (GABA-CB1-RS) showed that the distribution pattern and the subcellular CB1 receptor localization is maintained as it is observed in the wild-type hippocampus (Guti errez-Rodríguez et al., 2017; Remmers et al., 2017).”
BackgroundInfluentialRole of the endocannabinoid system in drug addiction
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“Coronal sections encompassing the LHb were obtained from CB1R-WT and CB1R-KO mice and a pre-embedding silver-intensified immunogold method was used for localization of the CB1R protein, as described (56).”
MethodHippocampal CB1 Receptors Control Incidental Associations
Busquets-García, A., da Cruz, J. F. O., Terral, G., Zottola, A. C. P., Gómez, E. S., Contini, A., Martin, H., Redon, B., Varilh, M., Ioannidou, C., et al. (2018) · Neuron · doi:10.1016/j.neuron.2018.08.014 · Cited by 62 · see citing works
Endocannabinoid signaling in brain diseases: Emerging relevance of glial cells
Bernal‐Chico, A., Tepavčević, V., Manterola, A., Utrilla, C. L., Matute, C., & Mato, S. (2022) · Glia · doi:10.1002/glia.24172 · Cited by 48 · see citing works
“applied to transgenic mice have allowed quantitative analysis of astrocytic CB1 topography in the mouse brain (Gutiérrez-Rodríguez et al., 2017; Gutiérrez-Rodríguez et al., 2018).”
BackgroundRemmers, F., Lange, M. D., Hamann, M., Ruehle, S., Pape, H., & Lutz, B. (2017) · Brain Structure and Function · doi:10.1007/s00429-017-1411-5 · Cited by 43 · see citing works
“This expression pattern is consistent with previous reports, where GABAergic neurons were shown to contain a large majority of brain CB1 receptor protein (Monory et al. 2006; Bellocchio et al. 2010; Gutiérrez-Rodríguez et al. 2017).”
ResultMolecular Alterations of the Endocannabinoid System in Psychiatric Disorders
Navarro, D., Gasparyan, A., Navarrete, F., Torregrosa, A. B., Rubio, G., Marín, M., Acosta, G. B., García‐Gutiérrez, M. S., & Manzanares, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094764 · Cited by 45 · see citing works
Peñasco, S., Rico‐Barrio, I., Puente, N., Gómez‐Urquijo, S., Fontaine, C. J., Huguet, J. E., Achicallende, S., Ramos, A., Reguero, L., Elezgarai, I., et al. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.04.020 · Cited by 39 · see citing works
“Interestingly, postsynaptic depolarization of DG granule cells can result in eCB release that suppresses glutamatergic inputs in the innermost 1/3 DML (Chiu and Castillo, 2008) where the CB1 receptor-containing commissural/ associational glutamatergic synapses converge (Gutiérrez-Rodríguez et al., 2017; Katona et al.,…”
InfluentialCannabinoid control of hippocampal functions: the where matters
Robledo, A., Vella, M., Grandes, P., & Gómez, E. S. (2021) · FEBS Journal · doi:10.1111/febs.15907 · Cited by 38 · see citing works
CB1 Receptors in the Anterior Piriform Cortex Control Odor Preference Memory
Terral, G., Busquets-García, A., Varilh, M., Achicallende, S., Cannich, A., Bellocchio, L., Río, I. B., Massa, F., Puente, N., Gómez, E. S., et al. (2019) · Current Biology · doi:10.1016/j.cub.2019.06.041 · Cited by 34 · see citing works
Peñasco, S., Rico-Barrio, I., Puente, N., Fontaine, C. J., Ramos, A., Reguero, L., Gerrikagoitia, I., de Fonseca, F. R., Suarez, J., Barrondo, S., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-019-0530-5 · Cited by 37 · see citing works
“A pre-embedding silver-intensified immunogold method was used for the localization of the CB1 receptor protein [24, 45].”
MethodRío, I. B., Puente, N., Peñasco, S., Rico, I., Gutiérrez‐Rodrίguez, A., Elezgarai, I., Ramos, A., Reguero, L., Gerrikagoitia, I., Christie, B. R., et al. (2017) · Addiction Biology · doi:10.1111/adb.12585 · Cited by 29 · see citing works
“pre-embedding immunogold method, as described previously (Gutiérrez-Rodríguez et al. 2017).”
BackgroundMethodResultInfluentialReceptor mechanisms underlying the CNS effects of cannabinoids: CB1 receptor and beyond
Hempel, B. J., & Xi, Z. (2022) · Advances in pharmacology · doi:10.1016/bs.apha.2021.10.006 · Cited by 29 · see citing works
Expression of Functional Cannabinoid Type-1 (CB1) Receptor in Mitochondria of White Adipocytes
Zottola, A. C. P., Severi, I., Cannich, A., Ciofi, P., Cota, D., Marsicano, G., Giordano, A., & Bellocchio, L. (2022) · Cells · doi:10.3390/cells11162582 · Cited by 28 · see citing works
CB2 Receptor Involvement in the Treatment of Substance Use Disorders
Navarrete, F., García‐Gutiérrez, M. S., Gasparyan, A., Navarro, D., & Manzanares, J. (2021) · Biomolecules · doi:10.3390/biom11111556 · Cited by 25 · see citing works
Río, I. B., Puente, N., Mimenza, A., Ramos, A., Serrano, M., Lekunberri, L., Gerrikagoitia, I., Christie, B. R., Nahirney, P. C., & Grandes, P. (2020) · The Journal of Comparative Neurology · doi:10.1002/cne.25098 · Cited by 22 · see citing works
“…CB1-Go-Af450, RRID:AB_2571592; guinea pig polyclonal, CB1-GP-Af530, RRID: AB_2571593; Table 2) has been extensively tested (Bénard et al., 2012; Bonilla-Del Rίo et al., 2019; Gutiérrez-Rodríguez et al., 2017; 2018; Hebert-Chatelain et al., 2016; Jimenez-Blasco et al., 2020; Puente et al., 2019).”
BackgroundMethodInfluentialCannabinoid Control of Olfactory Processes: The Where Matters
Terral, G., Marsicano, G., Grandes, P., & Gómez, E. S. (2020) · Genes · doi:10.3390/genes11040431 · Cited by 21 · see citing works
“Once produced, endocannabinoids act on CB1 receptors that are mainly described at pre-synaptic terminals [2,3,5], and other cellular locations [6].”
BackgroundGiacomo, V. D., Ruehle, S., Lutz, B., Häring, M., & Remmers, F. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108287 · Cited by 21 · see citing works
Fontaine, C. J., Gräfe, E. L., Pinar, C., Río, I. B., Grandes, P., & Christie, B. R. (2020) · Learning & Memory · doi:10.1101/lm.050666.119 · Cited by 19 · see citing works
Saumell-Esnaola, M., Barrondo, S., del Caño, G. G., Goicolea, M. A., Sallés, J., Lutz, B., & Monory, K. (2021) · Molecules · doi:10.3390/molecules26226897 · Cited by 18 · see citing works
“Although previous results using electron microscopy, a method that preserves the structure of the synapse, demonstrated that rescue strategies re-establish existing CB1 receptor levels expressed in glutamatergic and GABAergic cells [7], the accessibility of the CB1 receptor epitopes by large molecules such as antibodi…”
ResultA potential role of hippocampus on impulsivity and alcohol consumption through CB1R
Romero-Torres, B. M., Ramírez, Y. A. A., Duran-Alonzo, S. R., Ruiz‐Contreras, A. E., Herrera-Solís, A., Belmont, O. A., Prospero-Garcia, O. E., & Méndez‐Díaz, M. (2023) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2023.173558 · Cited by 17 · see citing works
Huguet, J. E., Río, I. B., Gómez‐Urquijo, S., Mimenza, A., Saumell-Esnaola, M., Roman, L. B., del Caño, G. G., Sallés, J., Puente, N., Gerrikagoitia, I., et al. (2021) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2021.645940 · Cited by 16 · see citing works
“, 2017), in contrast to its limited presence at excitatory glutamatergic terminals (Marsicano et al., 2003; Monory et al., 2006; Puente et al., 2011; Ruehle et al., 2013; Gutiérrez-Rodríguez et al., 2017), astrocytes (Stella, 2010; Han et al.”
BackgroundMethodAchicallende, S., Río, I. B., Serrano, M., Mimenza, A., Lekunberri, L., Lusar, I. A., Puente, N., Gerrikagoitia, I., & Grandes, P. (2022) · Histochemistry and Cell Biology · doi:10.1007/s00418-022-02139-4 · Cited by 16 · see citing works
Astroglial cannabinoid signaling and behavior
Ramon‐Duaso, C., Conde-Moro, A. R., & Busquets-García, A. (2022) · Glia · doi:10.1002/glia.24171 · Cited by 12 · see citing works
Almada, R. C., Falconi‐Sobrinho, L. L., da Silva, J. A., Wotjak, C. T., & Coimbra, N. C. (2022) · Psychopharmacology · doi:10.1007/s00213-022-06127-3 · Cited by 13 · see citing works
Huguet, J. E., Gómez, E. S., & Grandes, P. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413231 · Cited by 13 · see citing works
Eroli, F., Loonen, I. C. M., van den Maagdenberg, A. M. J. M., Tolner, E. A., & Nistri, A. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.12.013 · Cited by 12 · see citing works
“Though widely expressed in the central nervous system (Mackie, 2005), CB1Rs are distributed in a discrete manner in cortical layers (Guti errez-Rodríguez et al., 2017).”
BackgroundGiacomo, V. D., Ruehle, S., Lutz, B., Häring, M., & Remmers, F. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.15069 · Cited by 10 · see citing works
“For an overview of CB1 receptor expression patterns in the different mutant lines, see Table 1 and for their histological verification (see Gutiérrez-Rodríguez et al., 2017; Remmers et al., 2017; Ruehle et al., 2013; de Salas-Quiroga et al., 2015).”
BackgroundSerotonin 2A receptors and cannabinoids
Ibarra‐Lecue, I., Dı́ez-Alarcia, R., & Urigüen, L. (2021) · Progress in brain research · doi:10.1016/bs.pbr.2021.01.004 · Cited by 11 · see citing works
Martins, R. S., de Freitas, I. G., Sathler, M. F., Borges-Martins, V. P. P., Schitine, C., Sampaio, L. D. S., Freitas, H. R., Manhães, A. C., Pereira, M. D. S., Reis, R. A. D. M., et al. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.08.011 · Cited by 8 · see citing works
“Several studies have demonstrated that many axon terminals express CB1, mostly GABAergic, glutamatergic and noradrenergic cortical projections (Dos Anjos-Garcia et al., 2017; Gutierrez-Rodriguez et al., 2017; Reyes et al., 2015; Varodayan et al., 2016).”
Manterola, A., Chara, J. C., Aguado, T., Palazuelos, J., Matute, C., & Mato, S. (2022) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2022.1030060 · Cited by 7 · see citing works
“focused our analysis in the hippocampus because this structure exhibits high CB1 receptor levels and the precise localization of the CB1 protein has been analyzed in detail in this brain area by using EM (Hájos et al., 2000; Kawamura et al., 2006; Gutiérrez-Rodríguez et al., 2017; Gutiérrez-Rodríguez et al., 2018).”
BackgroundMethodResultInfluentialSalazar, I. B., Elezgarai, I., Rico‐Barrio, I., Gerrikagoitia, I., Puente, N., & Grandes, P. (2019) · The Journal of Comparative Neurology · doi:10.1002/cne.24808 · Cited by 7 · see citing works
“It remains to be elucidated the effect of CB1 receptor removal at GABAergic synapses where the receptor is expressed at much higher levels (Gutiérrez-Rodríguez et al., 2017).”
BackgroundMartín-Llorente, A., Serrano, M., Río, I. B., Lekunberri, L., Ocerin, G., Puente, N., Ramos, A., Rico‐Barrio, I., Gerrikagoitia, I., & Grandes, P. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242417316 · Cited by 7 · see citing works
“CB 1 -knockout (CB 1 -KO) mice were generated and genotyped as previously described [66] and formerly collected [30].”
BackgroundMethodInfluentialGenetic Tools in Rodents to Study Cannabinoid Functions
Monory, K., de Azúa, I. R., & Lutz, B. (2024) · Current topics in behavioral neurosciences · doi:10.1007/7854_2024_550 · Cited by 1 · see citing works
Non-neuronal targets for migraine therapy
Gliga, O., Feliu‐Soler, A., & Vila‐Pueyo, M. (2026) · Neurotherapeutics · doi:10.1016/j.neurot.2026.e00845 · Cited by 1 · see citing works
“Preclinical studies have shown the expression of the CB1 receptor in the membranes of astrocytes in rodents [43,44], but the expression of CB2 in these cells is negligible in the intact brain [45], although it can be induced in some inflammatory and pathological conditions [46,47].”
Fontaine, C. J. (2018) · UVic’s Research and Learning Repository (University of Victoria)
Behavioral Phenotyping From deleted CB1 Receptors on Cholinergic Neuron TerminalsPreprint
Wu, S., Tsutsui, K., & Fitoussi, A. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.06.495026
The endocannabinoid signalosome
Gerrikagoitia, I., Río, I. B.-D., Puente, N., & Grandes, P. (2025) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-443-13908-6.00007-4
Rodriguez, A. G. (2016) · theses.fr (ABES) · doi:10.70675/ecd0f3cbz19d7z406bza88eze6d1c4e9be0e
“terminals and density of CB1 receptors were detected between Glu-CB1-RS, CB1WT or GABA-CB1-KO (Gutiérrez-Rodríguez et al., 2016).”
BackgroundInfluentialImmunoelectron Microscopy of Brain Receptors: Focus on G Protein-Coupled Receptors
Bustinza, N. P., Río, I. B., Gómez‐Urquijo, S., Gerrikagoitia, I., & Grandes, P. (2026) · Neuromethods · doi:10.1007/978-1-0716-5456-9_3
- Authors
- Gutiérrez‐Rodríguez, A., Puente, N., Elezgarai, I., Ruehle, S., Lutz, B., Reguero, L., Gerrikagoitia, I., Marsicano, G., & Grandes, P.
- Affiliations
- Department of Neurosciences University of the Basque Country UPV/EHU E‐48940 Leioa Spain
- University of the Basque Country (ES)
- MRC Laboratory of Molecular Biology (GB)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- Université de Bordeaux (FR)
- Corresponding author
- Grandes, Pedro
- ORCID
- Venue
- Journal of Comparative Neurology
- Publisher
- Wiley
- Published
- 2016-07-08
- Volume
- 525
- Issue
- 2
- Pages
- 302-318
- ISSN
- 0021-9967 (ISSN-L)
- 1096-9861
- OpenAlex
- W2461893208
- Cited by
- 46
- References
- 78
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 9 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 9 · 2017: 4 · 2016: 1
- FWCI
- 4.86
- Type
- journal article
- Language
- en
- Open access
- green
- zenodo.org
- Licence
- Locations
- The Journal of Comparative Neurology (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- Institute of Infection and Immunity (RD12/0028/0004 (to P.G))
- Institut national de la santé et de la recherche médicale (EU‐Fp7 (to G.M.), PAINCAGE, HEALTH‐603191 (to G.M.))
- European Research Council (Endofood, ERC‐2010‐StG‐260515 (to G.M.), CannaPreg, ERC‐2014‐PoC‐640923 (to G.M.))
- Fondation de l'Avenir pour la Recherche Médicale Appliquée (DRM20101220445 (to G.M.))
- Agence Nationale de la Recherche (ANR Blanc NeuroNutriSens ANR‐13‐BSV4‐0006 (to G.M.), BRAIN ANR‐10‐LABX‐0043 (to G.M.); Grant sponsor: Deutsche Forschungsgemeinschaft (DFG); Grant number: SFB‐TRR 58; subproject A04 (to B.L.))
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- CB1 receptor, cannabinoid type 1 receptor, knock-in mice, hippocampus, synapse localization, glutamatergic neurons, GABAergic neurons, dentate gyrus, CA1 stratum radiatum, endocannabinoid system, immunoelectron microscopy, conditional knockout mice, subcellular localization
- MeSH terms
- Animals, Female, Hippocampus, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Neurons, Microscopy, Immunoelectron, Receptor, Cannabinoid, CB1, Mice
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