{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T07:48:48Z","timestamp":1774079328796,"version":"3.50.1"},"reference-count":63,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T00:00:00Z","timestamp":1773878400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005969","name":"University of Bologna","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100005969","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian parent association \u201cCDKL5 Insieme verso la cura\u201d"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>CDKL5 Deficiency Disorder (CDD) is a severe neurodevelopmental encephalopathy characterized by early disruptions of synaptic maturation and network stability, leading to persistent motor, cognitive, and behavioral impairments. Given the role of the endocannabinoid system in synaptic development, neuroinflammation, and neuronal resilience, we investigated whether the sustained enhancement of endogenous 2-arachidonoylglycerol (2-AG) signaling via monoacylglycerol lipase (MAGL) inhibition could mitigate key pathological features in adult Cdkl5 knockout (KO) mice. Using an intermittent 6-week treatment, the MAGL inhibitor JZL184 robustly increased plasma 2-AG levels, reduced MAGL protein levels, and activated CB1-AKT signaling without evidence of receptor desensitization. Despite this clear pharmacodynamic efficacy, behavioral effects were domain-specific: neither dose ameliorated core behavioral deficits, although the higher dose selectively reduced stereotypic jumping and modestly improved cue-dependent associative memory. At the cellular level, JZL184 induced biologically meaningful effects, partially restoring dendritic spine maturation in the primary somatosensory cortex and increasing neuronal survival in the vulnerable CA1 hippocampal region. In contrast, microglial responses were dose-dependent and divergent, with the lower dose exerting anti-inflammatory effects, while the higher dose increased cortical microglial density and Allograft Inflammatory Factor-1 (AIF-1) expression, suggesting engagement of compensatory or off-target mechanisms. Overall, these findings show that MAGL inhibition activates neuroprotective pathways and ameliorates select structural deficits in adult Cdkl5 KO mice, but is insufficient to produce broad behavioral recovery, highlighting the domain-specific effects of selective 2-AG enhancement via MAGL inhibition and the need for developmentally informed or multimodal therapeutic strategies in CDD.<\/jats:p>","DOI":"10.3390\/ijms27062773","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T08:54:37Z","timestamp":1773910477000},"page":"2773","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Endocannabinoid Enhancement via MAGL Inhibition in CDKL5 Deficiency: Selective Cellular Benefits and Domain-Specific Functional Effects in Adult Cdkl5 KO Mice"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6179-7610","authenticated-orcid":false,"given":"Manuela","family":"Loi","sequence":"first","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3066-0945","authenticated-orcid":false,"given":"Nicola","family":"Mottolese","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgio","family":"Medici","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feliciana","family":"Iannibelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7302-1246","authenticated-orcid":false,"given":"Nicol\u00f2","family":"Interino","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5029-9594","authenticated-orcid":false,"given":"Giulia","family":"Candini","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Federica","family":"Trebbi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angelica Marina","family":"Bove","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Fiori","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy"},{"name":"Department of Chemistry \u201cG. Ciamician\u201d, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2623-2769","authenticated-orcid":false,"given":"Stefania","family":"Trazzi","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3130-5168","authenticated-orcid":false,"given":"Elisabetta","family":"Ciani","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Science, University of Bologna, 40126 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/ejhg.2012.156","article-title":"The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy","volume":"21","author":"Fehr","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.pediatrneurol.2019.03.017","article-title":"Severity Assessment in CDKL5 Deficiency Disorder","volume":"97","author":"Demarest","year":"2019","journal-title":"Pediatr. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1111\/epi.16285","article-title":"CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development","volume":"60","author":"Demarest","year":"2019","journal-title":"Epilepsia"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13023-016-0418-y","article-title":"Prevalence and onset of comorbidities in the CDKL5 disorder differ from Rett syndrome","volume":"11","author":"Mangatt","year":"2016","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1042\/BST20220791","article-title":"CDKL5 deficiency disorder: Molecular insights and mechanisms of pathogenicity to fast-track therapeutic development","volume":"50","author":"Massey","year":"2022","journal-title":"Biochem. Soc. Trans."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1007\/s00431-023-05006-z","article-title":"Research progress on the pathogenesis of CDKL5 pathogenic variants and related encephalopathy","volume":"182","author":"Sun","year":"2023","journal-title":"Eur. J. Pediatr."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Amendola, E., Zhan, Y., Mattucci, C., Castroflorio, E., Calcagno, E., Fuchs, C., Lonetti, G., Silingardi, D., Vyssotski, A.L., and Farley, D. (2014). Mapping pathological phenotypes in a mouse model of CDKL5 disorder. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091613"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9726950","DOI":"10.1155\/2018\/9726950","article-title":"Heterozygous CDKL5 Knockout Female Mice Are a Valuable Animal Model for CDKL5 Disorder","volume":"2018","author":"Fuchs","year":"2018","journal-title":"Neural Plast."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2851","DOI":"10.1093\/hmg\/ddz102","article-title":"Site-specific abnormalities in the visual system of a mouse model of CDKL5 deficiency disorder","volume":"28","author":"Lupori","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Pizzo, R., Gurgone, A., Castroflorio, E., Amendola, E., Gross, C., Sassoe-Pognetto, M., and Giustetto, M. (2016). Lack of Cdkl5 Disrupts the Organization of Excitatory and Inhibitory Synapses and Parvalbumin Interneurons in the Primary Visual Cortex. Front. Cell Neurosci., 10.","DOI":"10.3389\/fncel.2016.00261"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/S1474-4422(22)00035-7","article-title":"CDKL5 deficiency disorder: Clinical features, diagnosis, and management","volume":"21","author":"Leonard","year":"2022","journal-title":"Lancet Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.eplepsyres.2019.02.001","article-title":"Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder","volume":"151","author":"Dale","year":"2019","journal-title":"Epilepsy Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1515\/revneuro-2024-0114","article-title":"The role of the endocannabinoid system in the pathogenesis and treatment of epilepsy","volume":"36","author":"Kosenkov","year":"2025","journal-title":"Rev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lowe, H., Toyang, N., Steele, B., Bryant, J., and Ngwa, W. (2021). The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179472"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1124\/pharmrev.122.000600","article-title":"Goods and Bads of the Endocannabinoid System as a Therapeutic Target: Lessons Learned after 30 Years","volume":"75","author":"Maccarrone","year":"2023","journal-title":"Pharmacol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100070","DOI":"10.1016\/j.pharmr.2025.100070","article-title":"The endocannabinoidomes: Pharmacological redundancy and promiscuity, and multi-kingdom variety of sources and molecular targets","volume":"77","author":"Iannotti","year":"2025","journal-title":"Pharmacol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Rodrigues, R.J., Marques, J.M., and Kofalvi, A. (2024). Cannabis, Endocannabinoids and Brain Development: From Embryogenesis to Adolescence. Cells, 13.","DOI":"10.20944\/preprints202410.1488.v1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1523\/JNEUROSCI.3101-05.2006","article-title":"The endocannabinoid system promotes astroglial differentiation by acting on neural progenitor cells","volume":"26","author":"Aguado","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23892","DOI":"10.1074\/jbc.M700678200","article-title":"The CB1 cannabinoid receptor mediates excitotoxicity-induced neural progenitor proliferation and neurogenesis","volume":"282","author":"Aguado","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1126\/science.1137406","article-title":"Hardwiring the brain: Endocannabinoids shape neuronal connectivity","volume":"316","author":"Berghuis","year":"2007","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3337","DOI":"10.1111\/ejn.16350","article-title":"Cannabidiol attenuates seizure susceptibility and behavioural deficits in adult CDKL5(R59X) knock-in mice","volume":"59","author":"Li","year":"2024","journal-title":"Eur. J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.1002\/epi4.70149","article-title":"Real-world efficacy and safety of cannabidiol in developmental and epileptic encephalopathies","volume":"10","author":"Perulli","year":"2025","journal-title":"Epilepsia Open"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Massey, S., Quigley, A., Rochfort, S., Christodoulou, J., and Van Bergen, N.J. (2024). Cannabinoids and Genetic Epilepsy Models: A Review with Focus on CDKL5 Deficiency Disorder. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms251910768"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1080\/13543776.2021.1841166","article-title":"An updated patent review of monoacylglycerol lipase (MAGL) inhibitors (2018-present)","volume":"31","author":"Bononi","year":"2021","journal-title":"Expert. Opin. Ther. Pat."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.chembiol.2009.05.009","article-title":"Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism","volume":"16","author":"Long","year":"2009","journal-title":"Chem. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"764","DOI":"10.14336\/AD.2020.0827","article-title":"Age-Related Cognitive and Motor Decline in a Mouse Model of CDKL5 Deficiency Disorder is Associated with Increased Neuronal Senescence and Death","volume":"12","author":"Gennaccaro","year":"2021","journal-title":"Aging Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111310","DOI":"10.1016\/j.pnpbp.2025.111310","article-title":"Fear conditioning: Insights into learning, memory and extinction and its relevance to clinical disorders","volume":"138","author":"Trent","year":"2025","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"21516","DOI":"10.1073\/pnas.1216988110","article-title":"Loss of CDKL5 disrupts kinome profile and event-related potentials leading to autistic-like phenotypes in mice","volume":"109","author":"Wang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1038\/nn.2616","article-title":"Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system","volume":"13","author":"Schlosburg","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nchembio.129","article-title":"Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects","volume":"5","author":"Long","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.celrep.2019.03.078","article-title":"Endocannabinoid Signaling Mediates Local Dendritic Coordination between Excitatory and Inhibitory Synapses","volume":"27","author":"Hu","year":"2019","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.biopsych.2015.08.028","article-title":"Dendritic Spine Instability in a Mouse Model of CDKL5 Disorder Is Rescued by Insulin-like Growth Factor 1","volume":"80","author":"Putignano","year":"2016","journal-title":"Biol. Psychiatry"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3887","DOI":"10.1093\/hmg\/ddw231","article-title":"HDAC4: A key factor underlying brain developmental alterations in CDKL5 disorder","volume":"25","author":"Trazzi","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"30101","DOI":"10.1074\/jbc.M804613200","article-title":"CDKL5 expression is modulated during neuronal development and its subcellular distribution is tightly regulated by the C-terminal tail","volume":"283","author":"Rusconi","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1385\/NMM:7:1-2:037","article-title":"Cannabinoid receptors and their role in neuroprotection","volume":"7","year":"2005","journal-title":"Neuromolecular Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7420","DOI":"10.1523\/JNEUROSCI.0539-17.2017","article-title":"Loss of CDKL5 in Glutamatergic Neurons Disrupts Hippocampal Microcircuitry and Leads to Memory Impairment in Mice","volume":"37","author":"Tang","year":"2017","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2244","DOI":"10.1007\/s12035-020-01884-8","article-title":"Increased DNA Damage and Apoptosis in CDKL5-Deficient Neurons","volume":"57","author":"Loi","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.neuropharm.2008.07.037","article-title":"Endocannabinoid signaling in microglial cells","volume":"56","author":"Stella","year":"2009","journal-title":"Neuropharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kasatkina, L.A., Rittchen, S., and Sturm, E.M. (2021). Neuroprotective and Immunomodulatory Action of the Endocannabinoid System under Neuroinflammation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115431"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Lysenko, L.V., Kim, J., Henry, C., Tyrtyshnaia, A., Kohnz, R.A., Madamba, F., Simon, G.M., Kleschevnikova, N.E., Nomura, D.K., and Ezekowitz, R.A. (2014). Monoacylglycerol lipase inhibitor JZL184 improves behavior and neural properties in Ts65Dn mice, a model of down syndrome. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114521"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5022","DOI":"10.1007\/s12035-024-04606-6","article-title":"Augmentation of Endogenous 2-Arachidonoylglycerol Mitigates Autistic Behaviors of BTBR Mice","volume":"62","author":"Zou","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lopez-Moraga, A., Beckers, T., and Luyten, L. (2022). The effects of stress on avoidance in rodents: An unresolved matter. Front. Behav. Neurosci., 16.","DOI":"10.3389\/fnbeh.2022.983026"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/nrn4036","article-title":"The endocannabinoid system in guarding against fear, anxiety and stress","volume":"16","author":"Lutz","year":"2015","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"4740","DOI":"10.1523\/JNEUROSCI.0054-06.2006","article-title":"Localization of diacylglycerol lipase-alpha around postsynaptic spine suggests close proximity between production site of an endocannabinoid, 2-arachidonoyl-glycerol, and presynaptic cannabinoid CB1 receptor","volume":"26","author":"Yoshida","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.plipres.2018.05.002","article-title":"2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain","volume":"71","author":"Baggelaar","year":"2018","journal-title":"Prog. Lipid Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bietar, B., Tanner, S., and Lehmann, C. (2023). Neuroprotection and Beyond: The Central Role of CB1 and CB2 Receptors in Stroke Recovery. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242316728"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"9742","DOI":"10.1523\/JNEUROSCI.22-22-09742.2002","article-title":"Cannabinoids promote oligodendrocyte progenitor survival: Involvement of cannabinoid receptors and phosphatidylinositol-3 kinase\/Akt signaling","volume":"22","author":"Vela","year":"2002","journal-title":"J. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Sanchez-Alegria, K., Flores-Leon, M., Avila-Munoz, E., Rodriguez-Corona, N., and Arias, C. (2018). PI3K Signaling in Neurons: A Central Node for the Control of Multiple Functions. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19123725"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Li, Z.H., Cheng, L., Wen, C., Ding, L., You, Q.Y., and Zhang, S.B. (2022). Activation of CNR1\/PI3K\/AKT Pathway by Tanshinone IIA Protects Hippocampal Neurons and Ameliorates Sleep Deprivation-Induced Cognitive Dysfunction in Rats. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.823732"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s12974-021-02204-0","article-title":"Inhibition of microglia overactivation restores neuronal survival in a mouse model of CDKL5 deficiency disorder","volume":"18","author":"Galvani","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Tassinari, M., Mottolese, N., Galvani, G., Ferrara, D., Gennaccaro, L., Loi, M., Medici, G., Candini, G., Rimondini, R., and Ciani, E. (2022). Luteolin Treatment Ameliorates Brain Development and Behavioral Performance in a Mouse Model of CDKL5 Deficiency Disorder. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158719"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1126\/science.1209200","article-title":"Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation","volume":"334","author":"Nomura","year":"2011","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.neuron.2012.09.020","article-title":"Endocannabinoid signaling and synaptic function","volume":"76","author":"Castillo","year":"2012","journal-title":"Neuron"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1152\/physrev.00019.2008","article-title":"Endocannabinoid-mediated control of synaptic transmission","volume":"89","author":"Kano","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"dev192161","DOI":"10.1242\/dev.192161","article-title":"Endocannabinoid signalling in stem cells and cerebral organoids drives differentiation to deep layer projection neurons via CB(1) receptors","volume":"147","author":"Aguareles","year":"2020","journal-title":"Development"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s11689-023-09475-z","article-title":"Role of the endocannabinoid system in fragile X syndrome: Potential mechanisms for benefit from cannabidiol treatment","volume":"15","author":"Palumbo","year":"2023","journal-title":"J. Neurodev. Disord."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nm.3127","article-title":"Targeting the endocannabinoid system in the treatment of fragile X syndrome","volume":"19","author":"Guegan","year":"2013","journal-title":"Nat. Med."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Bach, S., Shovlin, S., Moriarty, M., Bardoni, B., and Tropea, D. (2021). Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions. Front. Cell Neurosci., 15.","DOI":"10.3389\/fncel.2021.764761"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41386-019-0518-1","article-title":"The complexity of pharmacology of cannabidiol (CBD) and its implications in the treatment of brain disorders","volume":"45","author":"Elsaid","year":"2020","journal-title":"Neuropsychopharmacology"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.yebeh.2018.05.013","article-title":"Open-label use of highly purified CBD (Epidiolex(R)) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes","volume":"86","author":"Devinsky","year":"2018","journal-title":"Epilepsy Behav."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1002\/epi4.70078","article-title":"Is highly purified cannabidiol a treatment opportunity for drug-resistant epilepsy in subjects with typical Rett syndrome and CDKL5 deficiency disorder?","volume":"10","author":"Vignoli","year":"2025","journal-title":"Epilepsia Open"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e28467","DOI":"10.1016\/j.heliyon.2024.e28467","article-title":"A UPLC-MS\/MS method for simultaneous determination of arachidonic acid, stearic acid, and related endocannabinoids in human plasma","volume":"10","author":"Qian","year":"2024","journal-title":"Heliyon"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2773\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:17:43Z","timestamp":1774070263000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,19]]},"references-count":63,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062773"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062773","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,19]]}}}