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

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

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.

MeSH terms

  • Adolescent
  • Animals
  • Animals, Newborn
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Cannabis / adverse effects
  • Cognition / drug effects
  • Cognition Disorders / metabolism
  • Disease Models, Animal
  • Dronabinol / adverse effects*
  • Dronabinol / metabolism
  • Hippocampus / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / drug effects*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Psychotic Disorders

Substances

  • Brain-Derived Neurotrophic Factor
  • Disc1 protein, mouse
  • Nerve Tissue Proteins
  • BDNF protein, human
  • Dronabinol