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Hum Mol Genet. 2017 Jul 1;26(13):2462-2471. doi: 10.1093/hmg/ddx139.

BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction.

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Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel.
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.
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.


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.

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