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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.

Author information

1
Laboratory of Neuroscience, Felsenstein Medical Research Center, Rabin Medical Center, Beilinson Campus, Sackler Faculty of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
2
Department of Physiology and Pharmacology, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, 69978 Tel Aviv, Israel.
3
Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler School of Medicine, Tel Aviv University, 49100 Petach Tikva, Israel.
4
Research Unit, Geha Mental Health Center, 49100 Petach Tikva, Israel.
5
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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.

PMID:
28402427
PMCID:
PMC6251614
DOI:
10.1093/hmg/ddx139
[Indexed for MEDLINE]
Free PMC Article

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