Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure
de Salas-Quiroga, Adán (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
García-Rincón, Daniel (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Gómez-Domínguez, Daniel (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
Valero, Manuel (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
Simón-Sánchez, Samuel (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Paraíso-Luna, Juan (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Aguareles, José (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Pujadas, Mitona (Institut Hospital del Mar d'Investigacions Mèdiques)
Muguruza, Carolina (Euskal Herriko Unibertsitatea)
Callado, Luis F. (Euskal Herriko Unibertsitatea)
Lutz, Beat (University Medical Center of the Johannes Gutenberg University Mainz. Institute of Physiological Chemistry)
Guzmán, Manuel (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
de la Prida, Liset Menéndez (Instituto Cajal (Consejo Superior de Investigaciones Científicas))
Galve-Roperh, Ismael (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	Prenatal exposure to Δ 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 CB receptors (CBR). 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 CBR 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 CBR 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.
Ayudas:	Instituto de Salud Carlos III PI18-00941 Ministerio de Ciencia e Innovación RTI2018-095311-B-100 Ministerio de Ciencia e Innovación BFU2015-66887-R Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR138 Ministerio de Economía y Competitividad BES-2013-064171
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Developmental neurogenesis ; Risk factors
Publicado en:	Neuropsychopharmacology, Vol. 45 (january 2020) , p. 877-886, ISSN 1740-634X

DOI: 10.1038/s41386-020-0621-3
PMID: 31982904

10 p, 3.6 MB

El registro aparece en las colecciones:
Artículos > Artículos de investigación
Artículos > Artículos publicados