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Cannabidiol modulates hippocampal genes involved in mitochondrial function, ribosome biogenesis, synapse organization, and chromatin modifications

Published online by Cambridge University Press:  26 March 2024

João P. D. Machado ,
Valéria de Almeida ,
Antonio W. Zuardi ,
Jaime E. C. Hallak ,
José A. Crippa  and
André S. Vieira Open the ORCID record for André S. Vieira [Opens in a new window]
João P. D. Machado
Affiliation:
Laboratory of Electrophysiology, Neurobiology and Behaviour, Dept Functional and Structural Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil
Valéria de Almeida
Affiliation:
Laboratory of Neuroproteomics,, Dept Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinsas, São Paulo, Brazil
Antonio W. Zuardi
Affiliation:
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil National Institute for Science and Technology – Translational Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
Jaime E. C. Hallak
Affiliation:
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil National Institute for Science and Technology – Translational Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
José A. Crippa
Affiliation:
Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil National Institute for Science and Technology – Translational Medicine, Rio de Janeiro, Rio de Janeiro, Brazil
André S. Vieira*
Affiliation:
Laboratory of Electrophysiology, Neurobiology and Behaviour, Dept Functional and Structural Biology, Institute of Biology, University of Campinas, Campinas, São Paulo, Brazil Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, São Paulo, Brazil
*
Corresponding author: André S. Vieira; Email: [email protected]
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Abstract

Background:

Cannabidiol (CBD) is one of the main cannabinoids present in Cannabis sativa female flowers. Previous investigation has already provided insights into the CBD molecular mechanism; however, there is no transcriptome data for CBD effects on hippocampal subfields. Here, we investigate transcriptomic changes in dorsal and ventral CA1 of adult mice hippocampus after 100 mg/kg of CBD administration (i.p.) for one or seven consecutive days.

Methods:

C57BL/6JUnib mice were treated with either vehicle or CBD for 1 or 7 days. The collected brains were sectioned, and the hippocampal sub-regions were laser microdissected for RNA-Seq analysis.

Results:

The transcriptome analysis following 7 days of CBD administration indicates the differential expression of 1559 genes in dCA1 and 2924 genes in vCA1. Furthermore, GO/KEGG analysis identified 88 significantly enriched biological process and 26 significantly enriched pathways for dCBD7, whereas vCBD7 revealed 128 enriched BPs and 24 pathways.

Conclusion:

This dataset indicates a widespread decrease of electron transport chain and ribosome biogenesis transcripts in CA1, while chromatin modifications and synapse organization transcripts were increased following CBD administration for 7 days.

Keywords

CBDRNA-Seqtranscriptomicslaser-capture microdissectionhippocampal subfields
Type
Short Communication
Information
Acta Neuropsychiatrica , Volume 36 , Issue 5 , October 2024 , pp. 330 - 336
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Copyright
© The Author(s), 2024. Published by Cambridge University Press on behalf of Scandinavian College of Neuropsychopharmacology

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References

Abame, MA, He, Y, Wu, S, Xie, Z, Zhang, J, Gong, X, Wu, C and Shen, J (2021) Chronic administration of synthetic cannabidiol induces antidepressant effects involving modulation of serotonin and noradrenaline levels in the hippocampus. Neuroscience Letters 744, 135594.CrossRefGoogle ScholarPubMed
Acker, DWM, Wong, I, Kang, M and Paradis, S (2018) Semaphorin 4D promotes inhibitory synapse formation and suppresses seizures in vivo. Epilepsia 59(6), 1257–1268.CrossRefGoogle ScholarPubMed
Anand, KS and Dhikav, V (2012) Hippocampus in health and disease: an overview. Annals of Indian Academy of Neurology 15(4), 239–246.Google ScholarPubMed
Athanasiou, A, Clarke, AB, Turner, AE, Kumaran, NM, Vakilpour, S, Smith, PA, Bagiokou, D, Bradshaw, TD, Westwell, AD, Fang, L, Lobo, DN, Constantinescu, CS, Calabrese, V, Loesch, A, Alexander, SPH, Clothier, RH, Kendall, DA and Bates, TE (2007) Cannabinoid receptor agonists are mitochondrial inhibitors: a unified hypothesis of how cannabinoids modulate mitochondrial function and induce cell death. Biochemical and Biophysical Research Communications 364(1), 131–137.CrossRefGoogle ScholarPubMed
Bénard, G, Massa, F, Puente, N, Lourenço, J, Bellocchio, L, Soria-Gómez, E, Matias, I, Delamarre, A, Metna-Laurent, M, Cannich, A, Hebert-Chatelain, E, Mulle, C, Ortega-Gutiérrez, S, Martín-Fontecha, M, Klugmann, M, Guggenhuber, S, Lutz, B, Gertsch, Jürg, Chaouloff, F, López-Rodríguez, Mía L, Grandes, P, Rossignol, R and Marsicano, G (2012) Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nature Neuroscience 15(4), 558–564.CrossRefGoogle ScholarPubMed
Brand, MD and Nicholls, DG (2011) Assessing mitochondrial dysfunction in cells. Biochemical Journal 435(2), 297–312.CrossRefGoogle ScholarPubMed
Britch, SC, Babalonis, S and Walsh, SL (2021) Cannabidiol: Pharmacology and Therapeutic Targets. Psychopharmacology 238(1), 9–28.CrossRefGoogle ScholarPubMed
Caccamo, A, Branca, C, Talboom, JS, Shaw, DM, Turner, D, Ma, L, Messina, A, Huang, Z, Wu, J and Oddo, S (2015) Reducing ribosomal protein S6 Kinase 1 expression improves spatial memory and synaptic plasticity in a mouse model of alzheimer’s disease. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 35(41), 14042–14056.CrossRefGoogle Scholar
Chen, PB, Kawaguchi, R, Blum, C, Achiro, JM, Coppola, G, O’Dell, TJ and Martin, KC (2017) Mapping gene expression in excitatory neurons during hippocampal late-phase long-term potentiation. Frontiers in Molecular Neuroscience 10, 39.CrossRefGoogle ScholarPubMed
Consroe, P, Benedito, MAC, Leite, JR, Carlini, EA and Mechoulam, R (1982) Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice. European Journal of Pharmacology 83(3-4), 293–298.CrossRefGoogle ScholarPubMed
Dando, I, Donadelli, M, Costanzo, C, Dalla Pozza, E, D’Alessandro, A, Zolla, L and Palmieri, M (2013) Cannabinoids inhibit energetic metabolism and induce AMPK-dependent autophagy in pancreatic cancer cells. Cell death & disease 4(6), e664.CrossRefGoogle ScholarPubMed
Darweesh, RS, Khamis, TN and El-Elimat, T (2020) The effect of cannabidiol on the pharmacokinetics of carbamazepine in rats. Naunyn-Schmiedeberg’s archives of pharmacology 393(10), 1871–1886.CrossRefGoogle ScholarPubMed
Dobin, A, Davis, CA, Schlesinger, F, Drenkow, J, Zaleski, C, Jha, S, Batut, P, Chaisson, M and Gingeras, TR (2013) STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29(1), 15–21.CrossRefGoogle ScholarPubMed
Dorszewska, J, Kozubski, W, Waleszczyk, W, Zabel, M and Ong, K (2020) Neuroplasticity in the pathology of neurodegenerative diseases. Neural plasticity 2020, 4245821.CrossRefGoogle ScholarPubMed
Duan, Y, Wang, S-H, Song, J, Mironova, Y, Ming, G-L, Kolodkin, AL and Giger, RJ (2014) Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells. ELife 3, e04390. DOI: 10.7554/eLife.04390.CrossRefGoogle Scholar
Duman, JG, Mulherkar, S, Tu, Y-K, X. Cheng, J and Tolias, KF (2015) Mechanisms for spatiotemporal regulation of Rho-GTPase signaling at synapses. Neuroscience Letters 601, 4–10.CrossRefGoogle ScholarPubMed
Elsaid, S, Kloiber, S and Le Foll, B (2019) Effects of cannabidiol (CBD) in neuropsychiatric disorders: a review of pre-clinical and clinical findings. Progress in molecular biology and translational science 167, 25–75.CrossRefGoogle ScholarPubMed
Fanselow, MS and Dong, H-W (2010) Are the dorsal and ventral hippocampus functionally distinct structures? Neuron 65(1), 7–19.CrossRefGoogle ScholarPubMed
Feng, J, Zhou, Y, Campbell, SL, Le, T, Li, E, Sweatt, J D, Silva, AJ and Fan, G (2010) Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nature Neuroscience 13(4), 423–430.CrossRefGoogle ScholarPubMed
Fišar, Z, Singh, N and Hroudová, J (2014) Cannabinoid-induced changes in respiration of brain mitochondria. Toxicology Letters 231(1), 62–71.CrossRefGoogle ScholarPubMed
Fogaça, MV, Campos, AC, Coelho, LD, Duman, RS and Guimarães, FS (2018) The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: role of neurogenesis and dendritic remodeling. Neuropharmacology 135, 22–33.CrossRefGoogle ScholarPubMed
Guard, SE, Chapnick, DA, Poss, ZC, Ebmeier, CC, Jacobsen, J, Nemkov, T, Ball, KA, Webb, KJ, Simpson, HL, Coleman, S, Bunker, E, Ramirez, A, Reisz, JA, Sievers, R, Stowell, MHB, D’Alessandro, A, Liu, X and Old, WM (2022) Multiomic analysis reveals disruption of cholesterol homeostasis by cannabidiol in human cell lines. Molecular & Cellular Proteomics 21(10), 100262.CrossRefGoogle ScholarPubMed
Hattori, T, Jakubovic, A and McGeer, PL (1972) Reduction in number of nuclear membrane-attached ribosomes in infant rat brain following acute 9 -tetrahydrocannabinol administration. Experimental Neurology 36(1), 207–211.CrossRefGoogle ScholarPubMed
Hyun, K, Jeon, J, Park, K and Kim, J (2017) Writing, erasing and reading histone lysine methylations. Experimental & Molecular Medicine 49(4), e324.CrossRefGoogle ScholarPubMed
Ibeas Bih, C, Chen, T, Nunn, AVW, Bazelot, M, Dallas, M and Whalley, BJ (2015) Molecular targets of cannabidiol in neurological disorders. Neurotherapeutics 12(4), 699–730. DOI: 10.1007/s13311-015-0377-3.CrossRefGoogle ScholarPubMed
Iffland, K and Grotenhermen, F (2017) An update on safety and side effects of cannabidiol: a review of clinical data and relevant animal studies. Cannabis and Cannabinoid Research 2(1):139–154. DOI: 10.1089/can.2016.0034.CrossRefGoogle ScholarPubMed
Jakubovic, A and McGeer, PL (1972) Inhibition of rat brain protein and nucleic acid synthesis by cannabinoids in vitro. Canadian Journal of Biochemistry 50(6), 654–662.CrossRefGoogle ScholarPubMed
Karpova, NN, Sales, AJ and Joca, SR (2017) Epigenetic basis of neuronal and synaptic plasticity. Current Topics in Medicinal Chemistry 17(7), 771–793.CrossRefGoogle ScholarPubMed
Kim, J-H, Lee, J, Lee, I-S, Lee, S and Cho, K (2017) Histone lysine methylation and neurodevelopmental disorders. International Journal of Molecular Sciences 18(7), 1404. DOI: 10.3390/ijms18071404.CrossRefGoogle ScholarPubMed
Kurihara, R, Tohyama, Y, Matsusaka, S, Naruse, H, Kinoshita, E, Tsujioka, T, Katsumata, Y and Yamamura, H (2006) Effects of peripheral cannabinoid receptor ligands on motility and polarization in neutrophil-like HL60 cells and human neutrophils. Journal of Biological Chemistry 281(18), 12908–12918.CrossRefGoogle ScholarPubMed
Kwan Cheung, KA, Peiris, H, Wallace, G, Holland, OJ and Mitchell, MD (2019) The interplay between the endocannabinoid system, epilepsy and cannabinoids. International Journal of Molecular Sciences 20(23), 6079. DOI: 10.3390/ijms20236079.CrossRefGoogle Scholar
LaPlant, Q, Vialou, V, Covington, HE, Dumitriu, D, Feng, J, Warren, BL, Maze, I, Dietz, DM, Watts, EL, Iñiguez, SD, Koo, JW, Mouzon, E, Renthal, W, Hollis, F, Wang, H, Noonan, MA, Ren, Y, Eisch, AJ, Bolaños, CA, Kabbaj, M, Xiao, G, Neve, RL, Hurd, YL, Oosting, RS, Fan, G, Morrison, JH and Nestler, EJ (2010) Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens. Nature Neuroscience 13(9), 1137–1143.CrossRefGoogle ScholarPubMed
Levenson, JM, Roth, TL, Lubin, FD, Miller, CA, Huang, I-C, Desai, P, Malone, LM and Sweatt, JD (2006) Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. Journal of Biological Chemistry 281(23), 15763–15773.CrossRefGoogle ScholarPubMed
Long, LE, Chesworth, R, Huang, X-F, McGregor, IS, Arnold, JC, Karl, T (2010) A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. The International Journal of Neuropsychopharmacology 13(7), 861–876.CrossRefGoogle ScholarPubMed
Long, LE, Chesworth, R, Huang, X-F, Wong, A, Spiro, A, McGregor, IS, Arnold, JC and Karl, T (2012) Distinct Neurobehavioural Effects of Cannabidiol in Transmembrane Domain Neuregulin 1 Mutant Mice, PloS One 7(4), e34129.CrossRefGoogle ScholarPubMed
Love, MI, Huber, W and Anders, S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biology 15(12), 550.CrossRefGoogle ScholarPubMed
Ma, H, Li, C, Wang, J, Zhang, X, Li, M, Zhang, R, Huang, Z and Zhang, Y (2021) Amygdala-hippocampal innervation modulates stress-induced depressive-like behaviors through AMPA receptors. Proceedings of the National Academy of Sciences of the United States of America 118(6), e2019409118. DOI: 10.1073/pnas.2019409118.CrossRefGoogle ScholarPubMed
Machado, JPD, Athie, MCP, Matos, AHB, Lopes-Cendes, I and Vieira, A (2022) The transcriptome of rat hippocampal subfields. IBRO Neuroscience Reports 13, 322–329.CrossRefGoogle ScholarPubMed
Madireddy, S and Madireddy, S (2023) Therapeutic strategies to ameliorate neuronal damage in epilepsy by regulating oxidative stress mitochondrial dysfunction, and neuroinflammation. Brain Sciences 13(5), 784. DOI: 10.3390/brainsci13050784.CrossRefGoogle ScholarPubMed
McClung, CA and Nestler, EJ (2008) Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology 33, 3–17.CrossRefGoogle ScholarPubMed
McPartland, JM, Glass, M and Pertwee, RG (2007) Meta-analysis of cannabinoid ligand binding affinity and receptor distribution: interspecies differences. British Journal of Pharmacology 152(5), 583–593.CrossRefGoogle ScholarPubMed
Muñoz-Lasso, DC, Romá-Mateo, C, Pallardó, FV and Gonzalez-Cabo, P (2020) Much more than a scaffold: cytoskeletal proteins in neurological disorders. Cells 9(2), 358. DOI: 10.3390/cells9020358.CrossRefGoogle ScholarPubMed
Murray, HD, Schneider, DA and Gourse, RL (2003) Control of rRNA expression by small molecules is dynamic and nonredundant. Molecular Cell 12(1), 125–134.CrossRefGoogle ScholarPubMed
Post, RM (1992) Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. The American journal of psychiatry 149(8), 999–1010.Google ScholarPubMed
Ren, G, Zhang, X, Li, Y, Ridout, K, Serrano-Serrano, ML, Yang, Y, Liu, A, Ravikanth, G, Nawaz, MA, Mumtaz, AS, Salamin, N, Fumagalli, L (2021) Large-scale whole-genome resequencing unravels the domestication history of Cannabis sativa . Science Advances 7(29), eabg2286. DOI: 10.1126/sciadv.abg2286.CrossRefGoogle ScholarPubMed
Rosenberg, T, Gal-Ben-Ari, S, Dieterich, DC, Kreutz, MR, Ziv, NE, Gundelfinger, ED and Rosenblum, K (2014) The roles of protein expression in synaptic plasticity and memory consolidation. Frontiers in Molecular Neuroscience 7, November): 86CrossRefGoogle ScholarPubMed
Roy, DM, Walsh, LA and Chan, TA (2014) Driver mutations of cancer epigenomes. Protein & Cell 5(4):265–96. DOI: 10.1007/s13238-014-0031-6.CrossRefGoogle ScholarPubMed
Sales, AJ, Guimarães, FS and Joca, SRL (2020) CBD modulates DNA methylation in the prefrontal cortex and hippocampus of mice exposed to forced swim. Behavioural Brain Research 388, 112627.CrossRefGoogle ScholarPubMed
Singh, N, Hroudová, J and Fišar, Z (2015) Cannabinoid-induced changes in the activity of electron transport chain complexes of brain mitochondria. Journal of Molecular Neuroscience 56(4), 926–931.CrossRefGoogle ScholarPubMed
Squire, LR, Genzel, L, Wixted, JT and Morris, RG (2015) Memory consolidation. Cold Spring Harbor Perspectives in Biology 7(8), a021766.CrossRefGoogle ScholarPubMed
Stankiewicz, TR and Linseman, DA (2014) Rho family GTPases: key players in neuronal development, neuronal survival, and neurodegeneration. Frontiers in cellular neuroscience 8, 314.CrossRefGoogle ScholarPubMed
Tedesco, L, Valerio, A, Dossena, M, Cardile, A, Ragni, M, Pagano, C, Pagotto, U, Carruba, MO, Vettor, R and Nisoli, E (2010) Cannabinoid receptor stimulation impairs mitochondrial biogenesis in mouse white adipose tissue, muscle, and liver: the role of eNOS, p38 MAPK, and AMPK pathways. Diabetes 59(11), 2826–2836.CrossRefGoogle ScholarPubMed
Valvassori, SS, Bavaresco, DV, Scaini, G, Varela, RB, Streck, EL, Chagas, MH, Hallak, JEC, Zuardi, AW, Crippa, JA and Quevedo, J (2013) Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain. Revista Brasileira de Psiquiatria 35(4), 380–386.CrossRefGoogle ScholarPubMed
von Wrede, R, Helmstaedter, C and Surges, R (2021) Cannabidiol in the treatment of epilepsy. Clinical Drug Investigation 41(3), 211–220.CrossRefGoogle ScholarPubMed
Wu, T, Hu, E, Xu, S, Chen, M, Guo, P, Dai, Z, Feng, T, Zhou, L, Tang, W, Zhan, L, Fu, X, Liu, S, Bo, X and Yu, G (2021) Cluster profiler 4.0: a universal enrichment tool for interpreting omics data. The Innovation 2(3), 100141. DOI: 10.1016/j.xinn.2021.100141.CrossRefGoogle Scholar
Xolalpa, W, Perez-Galan, P, S. Rodríguez, M and Roue, G (2013) Targeting the ubiquitin proteasome system: beyond proteasome inhibition. Current Pharmaceutical Design 19(22), 4053–4093.CrossRefGoogle ScholarPubMed
Zanelati, TV, Biojone, C, Moreira, FA, Guimarães, FS and Joca, SRL (2010) Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. British Journal of Pharmacology 159(1), 122–128.CrossRefGoogle ScholarPubMed
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