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

Hadar Segal-Gavish, Neta Gazit, Yael Barhum, Tali Ben-Zur, Michal Taler, Shay Henry Hornfeld, Irit Gil-Ad, Abraham Weizman, Inna Slutsky, Minae Niwa, Atsushi Kamiya, Akira Sawa, Daniel Offen, Ran Barzilay

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2462-2471
Number of pages10
JournalHuman Molecular Genetics
Volume26
Issue number13
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Segal-Gavish, H., Gazit, N., Barhum, Y., Ben-Zur, T., Taler, M., Hornfeld, S. H., Gil-Ad, I., Weizman, A., Slutsky, I., Niwa, M., Kamiya, A., Sawa, A., Offen, D., & Barzilay, R. (2017). BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction. Human Molecular Genetics, 26(13), 2462-2471. https://doi.org/10.1093/hmg/ddx139