The interaction between the main psychotropic ingredient of Cannabis, Δ9- tetrahydrocannabinol (THC), with the endogenous cannabinoid system (ECS) is a critical and underrated issue that deserves utmost attention. The ECS, indeed, contributes to the formation and regulation of excitatory and inhibitory (E/I) neuronal networks that in the hippocampus underly spatial memory. This study explored sex-specific consequences of prenatal exposure to THC in hippocampus-dependent memory and the underlying cellular and molecular contributors of synaptic plasticity and E/I homeostasis. Sprague Dawley dams were exposed to THC (2 mg/kg) or vehicle, from gestational day 5-20. The adolescent progeny of both sexes was tested for: spatial memory retrieval and flexibility in the Barnes Maze; mRNA expression of relevant players of hippocampal synaptic plasticity; density of cholecystokinin-positive basket cells (CCK+BCs) - a major subtype of hippocampal inhibitory interneurons; mRNA expression of the excitatory and inhibitory synaptic proteins neuroligins (Nlgns), as a proxy of synaptic efficiency. Our results show a sex-specific disruption in spatial memory retrieval and flexibility, a male-specific decrease in CCK+BCs density and increase in the expression of markers of neuroplasticity, and consistent changes in the expression of Nlgn-1 and 3 isoforms. Despite a delay in memory retrieval, flexibility of memory was spared in prenatally-THC-exposed female offspring as well as most of the markers of neuroplasticity; a sex-specific increase in CCK+BCs density, and a consistent expression of Nlgn-3 was observed. The current results highlight a major vulnerability to prenatal exposure to THC on memory processing in the male progeny, and sex-specific alterations in the E/I balance and synaptic plasticity.

ATEN Center University of Palermo Palermo Italy

Department of Biological Chemical and Pharmaceutical Sciences Technologies University of Palermo Palermo Italy

Department of Bioscience and Technology for Food Agriculture and Environment University of Teramo Teramo 64100 Italy

Department of Health Promotion Mother and Child Care Internal Medicine and Medical Specialties of Excellence G D'Alessandro University of Palermo Palermo Italy

Dept of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Fondazione Policlinico Universitario A Gemelli IRCSS Rome Italy

Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague Czechia

Pharmacology Section Department of Healthcare Surveillance and Bioethics Università Cattolica del Sacro Cuore Rome Italy

Psychedelics Research Centre National Institute of Mental Health Prague Czechia

University of Palermo Dept of Biomedicine Neuroscience and Advanced Diagnostics via del Vespro 129 Palermo 90127 Italy

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