Schizophrenia is a common and debilitating psychiatric disease, often presenting late in the second decade of life. The etiology of schizophrenia is multifactorial, with both genetic and environmental components increasing an individual's risk to develop schizophrenia. Accumulating evidence suggests that schizophrenia develops following the accumulation of progressive insults to the developing nervous system-that is, schizophrenia is a neurodevelopmental disease. Thus, to reduce the societal and individual burden of schizophrenia it is important to identify, understand the mechanisms, and to limit these insults. Work over the last two decades has identified early, heavy adolescent Cannabis use as a risk factor for developing schizophrenia. As the prefrontal cortex is maturing during adolescence, and deficits in prefrontal cortex function are prominent in schizophrenia, it is logical to hypothesize that Cannabis adversely impacts the developing adolescent prefrontal cortex. The primary psychoactive component of Cannabis is delta-9-tetrahydrocannabinol (THC). While THC modulates synaptic transmission, it also affects neurodevelopment. In a recent study on the effect of THC on adolescent eye blink conditioning in rats, we made the intriguing observation that low dose adolescent THC impaired the acquisition of eye blink conditioning, and also activated cerebellar microglia. Interestingly, both the impaired eye blink conditioning and microglial activation were absent when THC was co- administered with cannabidiol (CBD), a bioactive, but not overtly psychoactive occasional component of cannabis. In pilot experiments we have replicated the finding that adolescent, low-dose THC activates microglia in the prefrontal cortex via CB1 cannabinoid receptors and increases IL-6 mRNA. The increase in IL- 6 was prevented by concurrent cannabidiol. These results lead us to propose the following innovative hypotheses: (1) THC activates microglial cells in the adolescent prefrontal cortex, which may lead to impaired synaptic pruning, with long lasting effects on synaptic structure. (2) CBD counteracts the effects of THC and serves a protective role. We will evaluate these hypotheses through a series of targeted experiments aimed at elucidating the role and extent of THC activation of microglial cells and their impact on prefrontal cortex development. This will be accomplished by completing two specific aims: 1. Does adolescent THC permanently alter the mPFC transcriptome? 2. Will cannabidiol suppress neuroinflammation produced by THC? Completing these specific aims will define the extent, duration, and consequences of microglial activation in the prefrontal cortex following adolescent THC administration. This will lay the groundwork for future studies that will examine the implications of THC-induced microglial activation on PFC neuronal network activity and PFC-mediated behaviors.

Public Health Relevance

Heavy Cannabis use during early adolescence, a time when the prefrontal cortex is maturing, is associated with an increased risk for later psychotic disorders. This proposal will examine the hypothesis that THC (the primary psychoactive component of Cannabis) activates microglial cells, perturbing the normal development of the prefrontal cortex during this critical period.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Wu, Da-Yu
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Indiana University Bloomington
Schools of Arts and Sciences
United States
Zip Code
Kasten, Chelsea R; Zhang, Yanping; Mackie, Ken et al. (2018) Short-Term Genetic Selection for Adolescent Locomotor Sensitivity to Delta9-Tetrahydrocannabinol (THC). Behav Genet 48:224-235
Leishman, Emma; Manchanda, Meera; Thelen, Rachel et al. (2018) Cannabidiol's Upregulation of N-acyl Ethanolamines in the Central Nervous System Requires N-acyl Phosphatidyl Ethanolamine-Specific Phospholipase D. Cannabis Cannabinoid Res 3:228-241
Leishman, Emma; Murphy, Michelle; Mackie, Ken et al. (2018) ?9-Tetrahydrocannabinol changes the brain lipidome and transcriptome differentially in the adolescent and the adult. Biochim Biophys Acta Mol Cell Biol Lipids 1863:479-492