title: BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction.
abstract: Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-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.
authors.affiliation: Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
authors.forename: Hadar
authors.initials: H
authors.lastname: Segal-Gavish
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Neta
authors.initials: N
authors.lastname: Gazit
authors.affiliation: Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Barhum
authors.affiliation: Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Ben-Zur
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Taler
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
authors.forename: Shay Henry
authors.initials: SH
authors.lastname: Hornfeld
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Gil-Ad
authors.affiliation: Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.|Research Unit, Geha Mental Health Center, 49100 Petach Tikva, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Weizman
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Slutsky
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Minae
authors.initials: M
authors.lastname: Niwa
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamiya
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.affiliation: Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
authors.affiliation: Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.|Research Unit, Geha Mental Health Center, 49100 Petach Tikva, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Barzilay
mesh_terms: D000293:Adolescent; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002188:Cannabis / Q000009:adverse effects; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000378:metabolism; D004195:Disease Models, Animal; D013759:Dronabinol / Q000009:adverse effects* / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011618:Psychotic Disorders
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; C579455:BDNF protein, human; D013759:Dronabinol