Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure
dc.contributor.author | De Salas Quiroga, Adán | |
dc.contributor.author | García Rincón, Daniel | |
dc.contributor.author | Gómez Domínguez, Daniel | |
dc.contributor.author | Valero, Manuel | |
dc.contributor.author | Simón Sánchez, Samuel | |
dc.contributor.author | Paraíso Luna, Juan | |
dc.contributor.author | Aguareles, José | |
dc.contributor.author | Pujadas, Mitona | |
dc.contributor.author | Muguruza Millán, Carolina | |
dc.contributor.author | Callado Hernando, Luis Felipe | |
dc.contributor.author | Lutz, Beat | |
dc.contributor.author | Guzmán, Manuel | |
dc.contributor.author | Menéndez de la Prida, Liset | |
dc.contributor.author | Galve Roperh, Ismael | |
dc.date.accessioned | 2020-04-27T10:32:14Z | |
dc.date.available | 2020-04-27T10:32:14Z | |
dc.date.issued | 2020-04 | |
dc.identifier.citation | Neuropsychopharmacology 45(5) : 877-886 (2020) | es_ES |
dc.identifier.issn | 0893-133X | |
dc.identifier.issn | 1740-634X | |
dc.identifier.uri | http://hdl.handle.net/10810/42912 | |
dc.description.abstract | Prenatal exposure to Delta(9)-tetrahydrocannabinol (THC), the most prominent active constituent of cannabis, alters neurodevelopmental plasticity with a long-term functional impact on adult offspring. Specifically, THC affects the development of pyramidal neurons and GABAergic interneurons via cannabinoid CB1 receptors (CB1R). However, the particular contribution of these two neuronal lineages to the behavioral alterations and functional deficits induced by THC is still unclear. Here, by using conditional CB1R knockout mice, we investigated the neurodevelopmental consequences of prenatal THC exposure in adulthood, as well as their potential sex differences. Adult mice that had been exposed to THC during embryonic development showed altered hippocampal oscillations, brain hyperexcitability, and spatial memory impairment. Remarkably, we found a clear sexual dimorphism in these effects, with males being selectively affected. At the neuronal level, we found a striking interneuronopathy of CCK-containing interneurons in the hippocampus, which was restricted to male progeny. This THC-induced CCK-interneuron reduction was not evident in mice lacking CB1R selectively in GABAergic interneurons, thus pointing to a cell-autonomous THC action. In vivo electrophysiological recordings of hippocampal LFPs revealed alterations in hippocampal oscillations confined to the stratum pyramidale of CA1 in male offspring. In addition, sharp-wave ripples, a major high-frequency oscillation crucial for learning and memory consolidation, were also altered, pointing to aberrant circuitries caused by persistent reduction of CCK+ basket cells. Taken together, these findings provide a mechanistic explanation for the long-term interneuronopathy responsible for the sex-dimorphic cognitive impairment induced by prenatal THC. | es_ES |
dc.description.sponsorship | The authors declare no conflict of interest. This work was supported by grants PI18-00941 to IG-R cofinanced by the European Development Regional Fund "A way to achieve Europe"; RTI2018-095311-B-100 to MG, BFU2015-66887-R to LM-P, and 2017-SGR-138 to MP from the Generalitat de Catalunya. DG-R was supported by Fundacion Tatiana Perez de Guzman; DG-D was supported by a PhD fellowship from the Spanish Ministry of Economy and Competitiveness (BES-2013-064171). JP-L and JA were supported by FPI and FPU program fellowships, respectively (Ministerio de Educacion, Cultura y Deporte) and S. S-S. was supported by Fondo Social Europeo-YEI (CT101/18-CT102/18PEJD-2018-PRE/BMD-7933). CM is recipient of a Marie Curie program fellowship (747487). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | Nature | es_ES |
dc.relation | info:eu-repo/grantAgreement/MINECO/BES-2013-064171 | es_ES |
dc.relation | info:eu-repo/grantAgreement/EC/H2020/747487 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | sharp-wave ripples | es_ES |
dc.subject | maternal cannabis | es_ES |
dc.subject | gene-expression | es_ES |
dc.subject | brain | es_ES |
dc.subject | endocannabinoids | es_ES |
dc.subject | oscillations | es_ES |
dc.subject | cb1 | es_ES |
dc.subject | delta(9)-tetrahydrocannabinol | es_ES |
dc.subject | dysfunction | es_ES |
dc.subject | mechanisms | es_ES |
dc.title | Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/. | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://www.nature.com/articles/s41386-020-0621-3 | es_ES |
dc.contributor.funder | European Commission | |
dc.departamentoes | Farmacología | es_ES |
dc.departamentoeu | Farmakologia | es_ES |
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