Studies of Cannabidiol in Neurodevelopment

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Cannabidiol (CBD) is a terpenoid constituent of the cannabis plant that is currently enjoying popularity as an herbal and food additive with purported beneficial effects in the treatment of anxiety, sleep disorders, inflammation and pain. Epidemiological studies indicate that use of CBD-containing products is increasing, including among pregnant and lactating women. In spite of these trends, we know very little about the effects of CBD on the developing brain. The purpose of the studies in this exploratory project is to examine the consequences of CBD exposure during development on the functioning of the cerebellum in later life. The overall hypothesis of these studies is that exposure of developing neurons to CBD results in increased apoptosis and dysregulated outgrowth of axons and dendrites. The specific goals of this project are to explore this hypothesis in the cerebellum of mice. The premise of this project is supported by a few studies in the literature and by preliminary data from our laboratory demonstrating that CBD exposure in utero results in significant reductions in performance on the rotarod assay, indicative of loss of balance and coordination. In addition, we have found that direct exposure of cerebellar granule neurons (CGNs) in culture to CBD results in apoptosis and, at lower concentrations, inappropriate activation of glycogen synthase kinase 3ß (GSK3ß). GSK3ß regulates activity-dependent dendritic arborization in CGNs and its over-activation has been associated with loss of appropriate cell morphology and connections to targets. Thus, our preliminary data support the hypothesis that CBD can be neurotoxic to developing neurons in the cerebellum. A second goal of these studies is to explore the hypothesis that GPR55, a G protein coupled receptor that is antagonized by CBD, is the site of action for CBD to affect neuronal development. In the first aim, we will examine the effects of perinatal CBD exposure on several cerebellar-dependent behaviors and cerebellar morphology at several ages. We will study the hypothesis that GPR55 is the site of action of CBD to alter cerebellar function and determine whether GSK3ß phosphorylation is altered by in vivo exposure to CBD. We utilize a voluntary consumption method for the administration of CBD to pregnant mice and will measure the concentrations of CBD that result in the dam and pups using this approach. In the second aim, we will examine the mechanism by which CBD affects GSK3ß activity in cultured CGNs, focusing on the role of GPR55, and determine the effects of CBD on activity-dependent neuritic outgrowth in these neurons. Successful completion of these studies will provide important information regarding the role of CBD in neuronal maturation and will begin to address an important gap in our knowledge regarding the effects of perinatal CBD exposure on brain development.