RT Journal Article
T1 Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure
A1 Salas Quiroga, Adán de
A1 García-Rincón, Daniel
A1 Gómez-Domínguez, Daniel
A1 Valero, Manuel
A1 Simón-Sánchez, Samuel
A1 Paraíso-Luna, Juan
A1 Aguareles, José
A1 Pujadas, Mitona
A1 Muguruza, Carolina
A1 Callado, Luis F.
A1 Lutz, Beat
A1 Guzmán, Manuel
A1 Menéndez de la Prida, Liset
A1 Galve Roperh, Ismael
AB Prenatal exposure to Δ9 -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.
PB Springer Nature
SN 0893-133X, ESSN: 1740-634X
YR 2020
FD 2020-01-26
LK https://hdl.handle.net/20.500.14352/6345
UL https://hdl.handle.net/20.500.14352/6345
LA eng
NO Ministerio de Economía y Competitividad (MINECO)
NO Ministerio de Educación, Cultura y Deporte
NO Fondo Europeo de Desarrollo Regional (FEDER)
NO Generalitat de Catalunya.
NO Fondo Social Europeo(ESF)-YEI
NO Marie Curie Program
DS Docta Complutense
RD 8 may 2024