Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network.

Autor:	Sarikahya MH; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Cousineau SL; Departments of Chemistry and Biochemistry, Western University, London, Ontario, N6A 3K7, Canada., De Felice M; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Szkudlarek HJ; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Wong KKW; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., DeVuono MV; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Lee K; Departments of Physiology and Pharmacology and Obstetrics and Gynaecology, Western University, London, Ontario, N6A 5C1, Canada.; Children's Health Research Institute, St. Josephs Health Care,, London, Ontario, N6C 2R5, Canada., Rodríguez-Ruiz M; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Gummerson D; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Proud E; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Ng THJ; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Hudson R; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Jung T; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada., Hardy DB; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada.; Departments of Physiology and Pharmacology and Obstetrics and Gynaecology, Western University, London, Ontario, N6A 5C1, Canada.; Children's Health Research Institute, St. Josephs Health Care,, London, Ontario, N6C 2R5, Canada., Yeung KK; Departments of Chemistry and Biochemistry, Western University, London, Ontario, N6A 3K7, Canada., Schmid S; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada.; Department of Psychology, Western University, London, Ontario, N6A 3K7, Canada., Rushlow W; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada.; Lawson Health Research Institute, St. Josephs Health Care, London, Ontario, N6C 2R5, Canada.; Department of Psychiatry, Western University, London, Ontario, N6A 3K7, Canada., Laviolette SR; Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada. steven.laviolette@schulich.uwo.ca.; Department of Anatomy and Cell Biology, Western University, London, Ontario, N6A 3K7, Canada. steven.laviolette@schulich.uwo.ca.; Lawson Health Research Institute, St. Josephs Health Care, London, Ontario, N6C 2R5, Canada. steven.laviolette@schulich.uwo.ca.; Department of Psychiatry, Western University, London, Ontario, N6A 3K7, Canada. steven.laviolette@schulich.uwo.ca.
Jazyk:	angličtina
Zdroj:	Molecular psychiatry [Mol Psychiatry] 2023 Oct; Vol. 28 (10), pp. 4234-4250. Date of Electronic Publication: 2023 Aug 01.
DOI:	10.1038/s41380-023-02190-0
Abstrakt:	With increasing maternal cannabis use, there is a need to investigate the lasting impact of prenatal exposure to Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis, on cognitive/memory function. The endocannabinoid system (ECS), which relies on polyunsaturated fatty acids (PUFAs) to function, plays a crucial role in regulating prefrontal cortical (PFC) and hippocampal network-dependent behaviors essential for cognition and memory. Using a rodent model of prenatal cannabis exposure (PCE), we report that male and female offspring display long-term deficits in various cognitive domains. However, these phenotypes were associated with highly divergent, sex-dependent mechanisms. Electrophysiological recordings revealed hyperactive PFC pyramidal neuron activity in both males and females, but hypoactivity in the ventral hippocampus (vHIPP) in males, and hyperactivity in females. Further, cortical oscillatory activity states of theta, alpha, delta, beta, and gamma bandwidths were strongly sex divergent. Moreover, protein expression analyses at postnatal day (PD)21 and PD120 revealed primarily PD120 disturbances in dopamine D1R/D2 receptors, NMDA receptor 2B, synaptophysin, gephyrin, GAD67, and PPARα selectively in the PFC and vHIPP, in both regions in males, but only the vHIPP in females. Lastly, using matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we identified region-, age-, and sex-specific deficiencies in specific neural PUFAs, namely docosahexaenoic acid (DHA) and arachidonic acid (ARA), and related metabolites, in the PFC and hippocampus (ventral/dorsal subiculum, and CA1 regions). This study highlights several novel, long-term and sex-specific consequences of PCE on PFC-hippocampal circuit dysfunction and the potential role of specific PUFA signaling abnormalities underlying these pathological outcomes. (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze:	MEDLINE
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