PMID- 28402427 OWN - NLM STAT- MEDLINE DCOM- 20171031 LR - 20200505 IS - 1460-2083 (Electronic) IS - 0964-6906 (Print) IS - 0964-6906 (Linking) VI - 26 IP - 13 DP - 2017 Jul 1 TI - BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction. PG - 2462-2471 LID - 10.1093/hmg/ddx139 [doi] AB - Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations. CI - (c) The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com. FAU - Segal-Gavish, Hadar AU - Segal-Gavish H AD - Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. FAU - Gazit, Neta AU - Gazit N AD - Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel. FAU - Barhum, Yael AU - Barhum Y AD - Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. FAU - Ben-Zur, Tali AU - Ben-Zur T AD - Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. FAU - Taler, Michal AU - Taler M AD - Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. FAU - Hornfeld, Shay Henry AU - Hornfeld SH AD - Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. FAU - Gil-Ad, Irit AU - Gil-Ad I AD - Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. FAU - Weizman, Abraham AU - Weizman A AD - Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. AD - Research Unit, Geha Mental Health Center, 49100 Petach Tikva, Israel. FAU - Slutsky, Inna AU - Slutsky I AD - Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel. FAU - Niwa, Minae AU - Niwa M AD - Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Kamiya, Atsushi AU - Kamiya A AD - Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Sawa, Akira AU - Sawa A AD - Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Offen, Daniel AU - Offen D AD - Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. FAU - Barzilay, Ran AU - Barzilay R AD - Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel. AD - Research Unit, Geha Mental Health Center, 49100 Petach Tikva, Israel. LA - eng GR - P50 MH094268/MH/NIMH NIH HHS/United States GR - R21 DA040127/DA/NIDA NIH HHS/United States PT - Journal Article PL - England TA - Hum Mol Genet JT - Human molecular genetics JID - 9208958 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Disc1 protein, mouse) RN - 0 (Nerve Tissue Proteins) RN - 7171WSG8A2 (BDNF protein, human) RN - 7J8897W37S (Dronabinol) SB - IM MH - Adolescent MH - Animals MH - Animals, Newborn MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cannabis/adverse effects MH - Cognition/drug effects MH - Cognition Disorders/metabolism MH - Disease Models, Animal MH - Dronabinol/*adverse effects/metabolism MH - Hippocampus/metabolism MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Nerve Tissue Proteins/*drug effects/genetics/metabolism MH - Psychotic Disorders PMC - PMC6251614 EDAT- 2017/04/13 06:00 MHDA- 2017/11/01 06:00 PMCR- 2018/07/01 CRDT- 2017/04/13 06:00 PHST- 2017/02/15 00:00 [received] PHST- 2017/04/06 00:00 [accepted] PHST- 2017/04/13 06:00 [pubmed] PHST- 2017/11/01 06:00 [medline] PHST- 2017/04/13 06:00 [entrez] PHST- 2018/07/01 00:00 [pmc-release] AID - 3574683 [pii] AID - ddx139 [pii] AID - 10.1093/hmg/ddx139 [doi] PST - ppublish SO - Hum Mol Genet. 2017 Jul 1;26(13):2462-2471. doi: 10.1093/hmg/ddx139.