{"id":16471,"date":"2023-05-16T18:54:15","date_gmt":"2023-05-16T18:54:15","guid":{"rendered":"https:\/\/drugprevent.org.uk\/ppp\/?p=16471"},"modified":"2023-07-04T17:22:33","modified_gmt":"2023-07-04T17:22:33","slug":"thc-exposure-of-human-ipsc-neurons-impacts-genes-associated-with-neuropsychiatric-disorders","status":"publish","type":"post","link":"https:\/\/drugprevent.org.uk\/ppp\/2023\/05\/thc-exposure-of-human-ipsc-neurons-impacts-genes-associated-with-neuropsychiatric-disorders\/","title":{"rendered":"THC Exposure Of Human iPSC Neurons Impacts Genes Associated With Neuropsychiatric Disorders"},"content":{"rendered":"
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Abstract<\/span><\/h2>\n
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There is a strong association between cannabis use and schizophrenia but the underlying cellular links are poorly understood. Neurons derived from human-induced pluripotent stem cells (hiPSCs) offer a platform for investigating both baseline and dynamic changes in human neural cells. Here, we exposed neurons derived from hiPSCs to \u03949<\/sup>-tetrahydrocannabinol (THC), and identified diagnosis-specific differences not detectable in vehicle-controls. RNA transcriptomic analyses revealed that THC administration, either by acute or chronic exposure, dampened the neuronal transcriptional response following potassium chloride (KCl)-induced neuronal depolarization. THC-treated neurons displayed significant synaptic, mitochondrial, and glutamate signaling alterations that may underlie their failure to activate appropriately; this blunted response resembles effects previously observed in schizophrenia hiPSC- derived neurons. Furthermore, we show a significant alteration in THC-related genes associated with autism and intellectual disability, suggesting shared molecular pathways perturbed in neuropsychiatric disorders that are exacerbated by THC.<\/span><\/p>\n<\/div>\n<\/div>\n

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Conflict of interest statement<\/span><\/h3>\n
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The authors declare that they have no conflict of interest.<\/span>
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Fig. 1. THC treatment regulates genes involved in mitochondrial and glutamate pathways.\u00a0<\/strong><\/span><\/p>\n

a<\/b>\u00a0RNA sequencing of hiPSC-derived neurons reveals 497 genes (acute) and 810 genes (chronic) are significantly changed following THC exposure, including.\u00a0b<\/b>\u00a0genes involved in mitochondrial (e.g.,\u00a0COX7A2<\/i>,\u00a0MT-CO1<\/i>, and\u00a0MT-CO3<\/i>) and glutamate (e.g.,\u00a0GRID2<\/i>) pathways (Quantitative RT\u2013PCR (qRT\u2013PCR); Ordinary one-way ANOVA with Tukey\u2019s multiple comparisons test: *p<\/i>\u2009<\u20090.05.\u00a0n<\/i>\u2009=\u20095 (see qRT\u2013PCR, Ca\u2013Ce, Supplementary Table S1)). Ingenuity pathway analysis shows that mitochondrial oxidative phosphorylation is strongly altered after both acute\u00a0c<\/b>\u00a0and chronic\u00a0d<\/b>\u00a0THC exposure<\/span><\/div>\n

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Fig. 2. Postsynaptic density and ion channel genes are regulated by THC treatment.\u00a0<\/strong><\/span><\/p>\n

a<\/b>,\u00a0b<\/b>\u00a0Multiple postsynaptic density and ion channel genes are significantly altered in hiPSC-derived neurons following acute or chronic THC exposure, including the postsynaptic gene\u00a0HOMER1<\/i>\u00a0(Quantitative RT\u2013PCR (qRT\u2013PCR); Ordinary one-way ANOVA with Tukey\u2019s multiple comparisons test: *p<\/i>\u2009<\u20090.05.\u00a0n<\/i>\u2009=\u20095 (see qRT\u2013PCR, Ca\u2013Ce, Supplementary Table S1)).\u00a0c<\/b>\u00a0Network analysis combining all THC-related genes from acute and chronic THC treatment shows broad changes to fundamental cellular functions such as RNA biology, chromatin regulation and development<\/span><\/div>\n

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Fig. 3. Genes altered by THC treatment in hiPSC-derived neurons are significantly associated with autism and intellectual disability.\u00a0<\/strong><\/span><\/p>\n

a<\/b>\u00a0Venn diagram showing the overlap between THC-related genes and autism, intellectual disability and schizophrenia.\u00a0b<\/b>\u00a0THC-related genes are significantly related to autism and intellectual disability (p<\/i>-value\u2009<\u20090.05)<\/span><\/div>\n<\/div>\n<\/div>\n<\/div>\n

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Fig. 4. THC treatment results in neuronal hypo-excitability similar to observations using schizophrenia-associated neurons.\u00a0<\/strong><\/span><\/p>\n

a<\/b>\u00a0Venn diagram showing impaired transcriptional response following 50\u2009mM KCl treatment for 3\u2009h in THC exposure hiPSC-derived neurons.\u00a0b<\/b>\u00a0A similar decrease in significantly regulated transcripts following 50\u2009mM KCl for 3\u2009h is observed in schizophrenia-associated hiPSC-derived neurons.\u00a0c<\/b>\u00a0A cohort of 5 control (C1\u20135) and 4 schizophrenia-associated (SZ1-4) cases were used for (d<\/b>) candidate qRT\u2013PCR analysis investigating\u00a0COX7A2<\/i>,\u00a0GRID2<\/i>\u00a0and\u00a0HOMER1<\/i>\u00a0following acute THC exposure.\u00a0e<\/b>\u00a0Blunted effect of THC treatment can be seen in immediate early gene transcripts such as\u00a0NR4A1<\/i>\u00a0and (f<\/b>)\u00a0FOSB<\/i>\u00a0following KCl-induced activation (Quantitative RT\u2013PCR (qRT\u2013PCR); Ordinary one-way ANOVA with Tukey\u2019s multiple comparisons test: *p<\/i>\u2009<\u20090.05, **p<\/i>\u2009<\u20090.01, ***p<\/i>\u2009<\u20090.001, ****p<\/i>\u2009<\u20090.0001.\u00a0n<\/i>\u2009=\u20095 controls (see qRT\u2013PCR, Ca\u2013Ce, Supplementary Table S1);\u00a0n<\/i>\u2009=\u20094 schizophrenia (see qRT\u2013PCR, S1\u2013S4, Supplementary Table S1))<\/span><\/div>\n
<\/div>\n
Source: THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders – PubMed (nih.gov)<\/a> April 2018<\/span><\/div>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

Abstract There is a strong association between cannabis use and schizophrenia but the underlying cellular links are poorly understood. Neurons derived from human-induced pluripotent stem cells (hiPSCs) offer a platform for investigating both baseline and dynamic changes in human neural cells. Here, we exposed neurons derived from hiPSCs to \u03949-tetrahydrocannabinol (THC), and identified diagnosis-specific differences […]<\/p>\n","protected":false},"author":12,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[63,30,64],"tags":[],"class_list":["post-16471","post","type-post","status-publish","format-standard","hentry","category-brain-and-behaviour","category-cannabis-marijuana","category-health"],"_links":{"self":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts\/16471","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/users\/12"}],"replies":[{"embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/comments?post=16471"}],"version-history":[{"count":0,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/posts\/16471\/revisions"}],"wp:attachment":[{"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/media?parent=16471"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/categories?post=16471"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/drugprevent.org.uk\/ppp\/wp-json\/wp\/v2\/tags?post=16471"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}