Cannabinoid CB1 receptors have been shown to regulate wide array of functions ranging from homeostasis to the cognitive functioning but recent data support the hypothesis that astrocytes also operate as a mediator of synaptic plasticity and contribute to cognition and learning. The receptor heterogeneity plays a key role in understanding the molecular mechanisms underlying these processes. Despite the fact that the majority of CB1 receptors act on neurons, studies have revealed that cannabinoids have direct control over astrocytes, including energy generation and neuroprotection. The tripartite synapse connects astrocytes to neurons and allows them to interact with one another and the astrocytes are key players in synaptic plasticity, which is associated with cognitive functions. This review focuses on our growing understanding of the intricate functions of astroglial CB1 that underpin physiological brain function, and in Alzheimer's disease.

School of Pharmacy Faculty of Health Sciences University of Botswana Gaborone Botswana

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Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat. 1995;8:429–431. doi: 10.1002/ca.980080612. PubMed DOI

Rapaka D, Bitra VR, Challa SR, Adiukwu PC. mTOR signaling as a molecular target for the alleviation of Alzheimer’s disease pathogenesis. Neurochem Int. 2022;155:105311. doi: 10.1016/j.neuint.2022.105311. PubMed DOI

Scheltens P, Strooper BD, Kivipelto M, Holstege H, Chételat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer’s disease. Lancet. 2021;397:10284. doi: 10.1016/S0140-6736(20)32205-4. PubMed DOI PMC

Rapaka D, Bitra VR, Challa SR, Adiukwu PC. Potentiation of microglial endocannabinoid signaling alleviates neuroinflammation in Alzheimer’s disease. Neuropeptides. 2021;90:102196. doi: 10.1016/j.npep.2021.102196. PubMed DOI

Fakhoury M. Microglia and Astrocytes in Alzheimer’s Disease: Implications for Therapy. Curr Neuropharmacol. 2018;16:508–518. doi: 10.2174/1570159X15666170720095240. PubMed DOI PMC

Carter SF, Herholz K, Rosa-Neto P, Pellerin L, Nordberg A, Zimmer ER. Astrocyte Biomarkers in Alzheimer’s Disease. Trends Mol Med. 2019;25:77–95. doi: 10.1016/j.molmed.2018.11.006. PubMed DOI

Frost GR, Li YM. The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol. 2017;7:170228. doi: 10.1098/rsob.170228. PubMed DOI PMC

Arranz AM, De Strooper B. The role of astroglia in Alzheimer’s disease: pathophysiology and clinical implications. Lancet Neurol. 2019;18:406–414. doi: 10.1016/S1474-4422(18)30490-3. PubMed DOI

Pan J, Ma N, Yu B, Zhang W, Wan J. Transcriptomic profiling of microglia and astrocytes throughout aging. J Neuroinflammation. 2020;17:97. doi: 10.1186/s12974-020-01774-9. PubMed DOI PMC

Almad A, Maragakis NJ. A stocked toolbox for understanding the role of astrocytes in disease. Nat Rev Neurol. 2018;14:351–362. doi: 10.1038/s41582-018-0010-2. PubMed DOI

Oberheim NA, Goldman SA, Nedergaard M. Heterogeneity of astrocytic form and function. Methods Mol Biol. 2012;814:23–45. doi: 10.1007/978-1-61779-452-0_3. PubMed DOI PMC

Verkhratsky A, Olabarria M, Noristani HN, Yeh CY, Rodriguez JJ. Astrocytes in Alzheimer’s disease. Neurotherapeutics. 2010;7:399–412. doi: 10.1016/j.nurt.2010.05.017. PubMed DOI PMC

Wilhelmsson U, Bushong EA, Price DL, Smarr BL, Phung V, Terada M, Ellisman MH, Pekny M. Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. Proc Natl Acad Sci U S A. 2006;103:17513–17518. doi: 10.1073/pnas.0602841103. PubMed DOI PMC

Verkhratsky A, Zorec R, Rodriguez JJ, Parpura V. Astroglia dynamics in ageing and Alzheimer’s disease. Curr Opin Pharmacol. 2016;26:74–79. doi: 10.1016/j.coph.2015.09.011. PubMed DOI

Ma B, Buckalew R, Du Y, Kiyoshi CM, Alford CC, Wang W. Gap junction coupling confers isopotentiality on astrocyte syncytium. Glia. 2016;64:214–226. doi: 10.1002/glia.22924. PubMed DOI PMC

Parpura V, Basarsky TA, Liu F, Jeftinija K, Jeftinija S, Haydon PG. Glutamate-mediated astrocyte-neuron signalling. Nature. 1994;369:744–747. doi: 10.1038/369744a0. PubMed DOI

Mothet JP, Parent AT, Wolosker H, Brady RO, Jr, Linden DJ, Ferris CD, Rogawski MA, Snyder SH. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 2000;97:4926–4931. doi: 10.1073/pnas.97.9.4926. PubMed DOI PMC

Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, et al. Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci U S A. 1998;95:15735–15740. doi: 10.1073/pnas.95.26.15735. PubMed DOI PMC

Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006;440:1054–1059. doi: 10.1038/nature04671. PubMed DOI

Verkhratsky A, Nedergaard M, Hertz L. Why are astrocytes important? Neurochem Res. 2015;40:389–401. doi: 10.1007/s11064-014-1403-2. PubMed DOI

Fellin T. Communication between neurons and astrocytes:relevance to the modulation of synaptic and network activity. J Neurochem. 2009;108:533–544. doi: 10.1111/j.1471-4159.2008.05830.x. PubMed DOI

Santello M, Toni N, Volterra A. Astrocyte function from information processing to cognition and cognitive impairment. Nat Neurosci. 2019;22:154–156. doi: 10.1038/s41593-018-0325-8. PubMed DOI

Barros LF, San Martín A, Ruminot I, Sandoval PY, Fernández-Moncada I, Baeza-Lehnert F, Arce-Molina R, et al. Near-critical GLUT1 and neurodegeneration. J Neurosci Res. 2017;95:2267–2274. doi: 10.1002/jnr.23998. PubMed DOI

Masaki K. Recent advances in understanding connexin gap junction pathology in demyelinating diseases. Clin Exp Neuroimmunol. 2020;11(Suppl 1):4–13. doi: 10.1111/cen3.12577. DOI

Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar MW, Okamoto S, Okamoto S, Dziewczapolski G, et al. Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 2013;110:E2518–E2527. doi: 10.1073/pnas.1313546110. PubMed DOI PMC

Hefendehl JK, LeDue J, Ko RW, Mahler J, Murphy TH, MacVicar BA. Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging. Nat Commun. 2016;27:13441. doi: 10.1038/ncomms13441. PubMed DOI PMC

Haughey NJ, Mattson MP. Alzheimer’s amyloid beta-peptide enhances ATP/gap junction-mediated calcium-wave propagation in astrocytes. Neuromolecular Med. 2003;3:173–180. doi: 10.1385/NMM:3:3:173. PubMed DOI

Simpson JE, Ince PG, Shaw PJ, Heath PR, Raman R, Garwood CJ. Microarray analysis of the astrocyte transcriptome in the aging brain: relationship to Alzheimer’s pathology and APOE genotype. Neurobiol Aging. 2011;32:1795–1807. doi: 10.1016/j.neurobiolaging.2011.04.013. PubMed DOI

Guzman SJ, Gerevich Z. P2Y receptors in synaptic transmission and plasticity: therapeutic potential in cognitive dysfunction. Neural Plast. 2016;2016:1207393. doi: 10.1155/2016/1207393. PubMed DOI PMC

Ceyzériat K, Ben Haim L, Denizot A, Pommier D, Matos M, Guillemaud O, Palomares MA, et al. Modulation of astrocyte reactivity improves functional deficits in mouse models of Alzheimer’s disease. Acta Neuropathol Commun. 2018;6:104. doi: 10.1186/s40478-018-0606-1. PubMed DOI PMC

Reichenbach N, Delekate A, Plescher M, Schmitt F, Krauss S, Blank N, Halle A, Petzold GC. Inhibition of Stat3-mediated astrogliosis ameliorates pathology in an Alzheimer’s disease model. EMBO Mol Med. 2019;11:e9665. doi: 10.15252/emmm.201809665. PubMed DOI PMC

Schumann RR, Pfeil D, Freyer D, Buerger W, Lamping N, Kirschning CJ, Goebel UB, Weber JR. Lipopolysaccharide and pneumococcal cell wall components activate the mitogen activated protein kinases (MAPK) erk-1, erk-2, and p38 in astrocytes. Glia. 1998;22:295–305. doi: 10.1002/(SICI)1098-1136(199803)22:3<295::AID-GLIA8>3.0.CO;2-4. PubMed DOI

Correa F, Ljunggren E, Mallard C, Nilsson M, Weber SG, Sandberg M. The Nrf2-inducible antioxidant defense in astrocytes can be both up- and down-regulated by activated microglia: Involvement of p38 MAPK. Glia. 2011;59:785–799. doi: 10.1002/glia.21151. PubMed DOI PMC

Cui M, Huang Y, Tian C, Zhao Y, Zheng J. FOXO3a inhibits TNF-α- and IL-1β-induced astrocyte proliferation: Implication for reactive astrogliosis. Glia. 2011;59:641–654. doi: 10.1002/glia.21134. PubMed DOI PMC

Metna-Laurent M, Marsicano G. Rising stars: modulation of brain functions by astroglial type-1 cannabinoid receptors. Glia. 2015;63:353–364. doi: 10.1002/glia.22773. PubMed DOI

Specter S, Cabral G. Cannabinoids, immunity and resistance to infections. J Neuroimmunol. 1996;69:15–23. doi: 10.1016/0165-5728(96)00121-X. DOI

Howlett AC, Abood ME. CB1 and CB2 receptor pharmacology. Adv Pharmacol. 2017;80:169–206. doi: 10.1016/bs.apha.2017.03.007. PubMed DOI PMC

Schurman LD, Lu D, Kendall DA, Howlett AC, Lichtman AH. Molecular mechanism and cannabinoid pharmacology. Handb Exp Pharmacol. 2020;258:323–353. doi: 10.1007/164_2019_298. PubMed DOI PMC

Vaseghi S, Nasehi M, Zarrindast M-Reza. How do stupendous cannabinoids modulate memory processing via affecting neurotransmitter systems? Neurosci Biobehav Rev. 2021;120:173–221. doi: 10.1016/j.neubiorev.2020.10.018. PubMed DOI

Araujo DJ, Tjoa K, Saijo K. The endocannabinoid system as a window into micoglial biology and its relationship to autism. Front Cell Neurosci. 2019;13:424. doi: 10.3389/fncel.2019.00424. PubMed DOI PMC

Duffy SS, Hayes JP, Fiore NT, Moalem Taylor G. The cannabinoid system and microglia in health and disease. Neuropharmacology. 2021;190:108555. doi: 10.1016/j.neuropharm.2021.108555. PubMed DOI

Pertwee RG, Howlett AC, Abood ME, Alexander SPH, Di Marzo V, Elphick MR, Greasley PJ, et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: Beyond CB1and CB2. Pharmacol Rev. 2010;62:588–631. doi: 10.1124/pr.110.003004. PubMed DOI PMC

Elangovan S, Holsinger RMD. Cyclical amyloid beta-astrocyte activity induces oxidative stress in Alzheimer’s disease. Biochimie. 2020;171–172:38–42. doi: 10.1016/j.biochi.2020.02.003. PubMed DOI

Alasmari F, Alshammari MA, Alasmari AF, Alanazi WA, Alhazzani K. Neuroinflammatory cytokines induce amyloid beta neurotoxicity through modulating amyloid precursor protein levels/metabolism. Biomed Res Int. 2018;2018:3087475. doi: 10.1155/2018/3087475. PubMed DOI PMC

Zhao J, O’Connor T, Vassar R. The contribution of activated astrocytes to Aβ production: implications for Alzheimer’s disease pathogenesis. J Neuroinflammation. 2011;8:150. doi: 10.1186/1742-2094-8-150. PubMed DOI PMC

Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, Silverstein SC, Husemann J. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat Med. 2003;9:453–457. doi: 10.1038/nm838. PubMed DOI

Hegyi Z, Kis G, Hollo K, Ledent C, Antal M. Neuronal and glial localization of the cannabinoid-1 receptor in the superficial spinal dorsal horn of the rodent spinal cord. Eur J Neurosci. 2009;30:251–262. doi: 10.1111/j.1460-9568.2009.06816.x. PubMed DOI

Gutierrez-Rodriguez A, Bonilla-Del Rio I, Puente N, Gomez-Urquijo SM, Fontaine CJ, Egana-Huguet J, Elezgarai I, et al. Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus. Glia. 2018;66:1417–1431. doi: 10.1002/glia.23314. PubMed DOI

Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, Phatnani HP, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014;34:11929–11947. doi: 10.1523/JNEUROSCI.1860-14.2014. PubMed DOI PMC

Rodriguez JJ, Mackie K, Pickel VM. Ultrastructural localization of the CB1 cannabinoid receptor in mu-opioid receptor patches of the rat Caudate putamen nucleus. J Neurosci. 2001;21:823–833. doi: 10.1523/JNEUROSCI.21-03-00823.2001. PubMed DOI PMC

Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010;58:1017–1030. doi: 10.1002/glia.20983. PubMed DOI PMC

Covelo A, Eraso-Pichot A, Fernández-Moncada I, Serrat R, Marsicano G. CB1R-dependent regulation of astrocyte physiology and astrocyte-neuron interactions. Neuropharmacology. 2021;195:108678. doi: 10.1016/j.neuropharm.2021.108678. PubMed DOI

Han J, Kesner P, Metna-Laurent M, Duan T, Xu L, Georges F, Koehl M, et al. Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell. 2012;148:1039–1050. doi: 10.1016/j.cell.2012.01.037. PubMed DOI

Navarrete M, Araque A. Endocannabinoids mediate neuron-astrocyte communication. Neuron. 2008;57:883–893. doi: 10.1016/j.neuron.2008.01.029. PubMed DOI

Szabó GG, Lenkey N, Holderith N, Andrási T, Nusser Z, Hájos N. Presynaptic calcium channel inhibition underlies CB1 cannabinoid receptormediated suppression of GABA release. J Neurosci. 2014;34:7958–7963. doi: 10.1523/JNEUROSCI.0247-14.2014. PubMed DOI PMC

Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346:561–564. doi: 10.1038/346561a0. PubMed DOI

Shigetomi E, Jackson-Weaver O, Huckstepp RT, O’Dell TJ, Khakh BS. TRPA1 channels are regulators of astrocyte basal calcium levels and long-term potentiation via constitutive d-serine release. J Neurosci. 2013;33:10143–10153. doi: 10.1523/JNEUROSCI.5779-12.2013. PubMed DOI PMC

Ortega-Gutiérrez S, Molina-Holgado E, Guaza C. Effect of anandamide uptake inhibition in the production of nitric oxide and in the release of cytokines in astrocyte cultures. Glia. 2005;52:163–168. doi: 10.1002/glia.20229. PubMed DOI

Pacholko AG, Wotton CA, Bekar LK. Astrocytes-the ultimate effectors of long-range neuromodulatory networks? Front Cell Neurosci. 2020;14:581075. doi: 10.3389/fncel.2020.581075. PubMed DOI PMC

Verkhratsky A, Chvatal A. NMDA receptors in astrocytes. Neurochem Res. 2020;45:122–133. doi: 10.1007/s11064-019-02750-3. PubMed DOI

Covelo A, Araque A. Lateral regulation of synaptic transmission by astrocytes. Neuroscience. 2016;323:62–66. doi: 10.1016/j.neuroscience.2015.02.036. PubMed DOI

Andersson M, Blomstrand F, Hanse E. Astrocytes play a critical role in transient heterosynaptic depression in the rat hippocampal CA1 region. J Physiol. 2007;585:843–852. doi: 10.1113/jphysiol.2007.142737. PubMed DOI PMC

Zhu PJ, Lovinger DM. Persistent synaptic activity produces long-lasting enhancement of endocannabinoid modulation and alters long-term synaptic plasticity. J Neurophysiol. 2007;97:4386–4389. doi: 10.1152/jn.01228.2006. PubMed DOI

Martín R, Bajo-Graneras R, Moratalla R, Perea G, Araque A. Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways. Science. 2015;349:730–734. doi: 10.1126/science.aaa7945. PubMed DOI

Wilson RI, Nicoll RA. Endocannabinoid signaling in the brain. Science. 2002;296:678–682. doi: 10.1126/science.1063545. PubMed DOI

Gómez-Gonzalo M, Navarrete M, Perea G, Covelo A, Martín-Fernández M, Shigemoto R, Luján R, Araque A. Endocannabinoids induce lateral long-term potentiation of transmitter release by stimulation of gliotransmission. Cereb Cortex. 2015;25:3699–3712. doi: 10.1093/cercor/bhu231. PubMed DOI

Heifets BD, Castillo PE. Endocannabinoid signaling and long-term synaptic plasticity. Annu Rev Physiol. 2009;71:283–306. doi: 10.1146/annurev.physiol.010908.163149. PubMed DOI PMC

Min R, Nevian T. Astrocyte signaling controls spike timing dependent depression at neocortical synapses. Nat Neurosci. 2012;15:746–753. doi: 10.1038/nn.3075. PubMed DOI

Sjöström PJ, Turrigiano GG, Nelson SB. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors. Neuron. 2003;39:641–654. doi: 10.1016/S0896-6273(03)00476-8. PubMed DOI

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541:481–487. doi: 10.1038/nature21029. PubMed DOI PMC

Adamsky A, Kol A, Kreisel T, Doron A, Ozeri-Engelhard N, Melcer T, Refaeli R, et al. Astrocytic activation generates de novo neuronal potentiation and memory enhancement. Cell. 2018;174:59–71.e14. doi: 10.1016/j.cell.2018.05.002. PubMed DOI

Schurman LD, Carper MC, Moncayo LV, Ogasawara D, Richardson K, Yu L. Diacylglycerol lipase-alpha regulates hippocampal-dependent learning and memory processes in mice. J Neurosci. 2019;39:5949–5965. doi: 10.1523/JNEUROSCI.1353-18.2019. PubMed DOI PMC

Froger N, Orellana JA, Cohen-Salmon M, Ezan P, Amigou E, Saez JC, Giaume C. Cannabinoids prevent the opposite regulation of astroglial connexin43 hemichannels and gap junction channels induced by proinflammatory treatments. J Neurochem. 2009;111:1383–1397. doi: 10.1111/j.1471-4159.2009.06407.x. PubMed DOI

Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009;89:309–380. doi: 10.1152/physrev.00019.2008. PubMed DOI

Verkhratsky A, Nedergaard M. Physiology of astroglia. Physiol Rev. 2018;98:239–389. doi: 10.1152/physrev.00042.2016. PubMed DOI PMC

Robin LM, Oliveira da Cruz JF, Langlais VC, Martin-Fernandez M, Metna-Laurent M, Busquets-Garcia A, Bellocchio L, et al. Astroglial CB1 receptors determine synaptic D-serine availability to enable recognition memory. Neuron. 2018;98:935–944. doi: 10.1016/j.neuron.2018.04.034. PubMed DOI

Rasooli-Nejad S, Palygin O, Lalo U, Pankratov Y. Cannabinoid receptors contribute to astroglial Ca2+-signalling and control of synaptic plasticity in the neocortex. Philos Trans R Soc Lond B Biol Sci. 2014;369:20140077. doi: 10.1098/rstb.2014.0077. PubMed DOI PMC

Lorıa F, Petrosino S, Hernangomez M, Mestre L, Spagnolo A, Correa F, Di Marzo V, Docagne F, Guaza C. An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis. Neurobiol Dis. 2010;37:166–176. doi: 10.1016/j.nbd.2009.09.020. PubMed DOI

Tourino C, Zimmer A, Valverde O. THC prevents MDMA neurotoxicity in mice. PLoS One. 2010;5:e9143. doi: 10.1371/journal.pone.0009143. PubMed DOI PMC

Sheng WS, Hu S, Min X, Cabral GA, Lokensgard JR, Peterson PK. Synthetic cannabinoid WIN55,212–2 inhibits generation of inflammatory mediators by IL-1beta-stimulated human astrocytes. Glia. 2005;49:211–219. doi: 10.1002/glia.20108. PubMed DOI

Rapaka D, Bitra VR, Ummidi R, Akula A. Benincasa hispida alleviates amyloid pathology by inhibition of Keap1/Nrf2-axis: Emphasis on oxidative and inflammatory stress involved in Alzheimer’s disease model. Neuropeptides. 2021;88:102151. doi: 10.1016/j.npep.2021.102151. PubMed DOI

Berberine Exerts Neuroprotective Effects in Alzheimer's Disease by Switching Microglia M1/M2 Polarization Through PI3K-AKT Signaling