Cannabis is the most commonly used illicit drug during pregnancy and its use during this time is associated with an increased risk of adverse neurological and developmental outcomes in exposed children. This suggests that the most abundant active component of cannabis, ?9-tetrahydrocannabinol (THC), may affect nervous system development. While the cerebellum was once thought to be primarily involved in coordination of motor movement, several recent studies indicate that it is involved in a range of sophisticated behaviors, including cognition. In addition, cerebellar dysfunction is found in neurodevelopmental disorders including autism and schizophrenia. Thus, a better understanding of how environmental and genetic factors (both implicated in neurodevelopmental disorders) impact cerebellar development is clearly warranted. The proposed study will examine roles of the endogenous cannabinoid system on cerebellar development, and how THC affects this process. While THC can detrimentally impact cerebral cortical development, little is known on the role of endogenous cannabinoids and THC in cerebellar development. In preliminary studies using CB1 receptor knockout mice we find a strikingly abnormal foliation of the anterior lobe of the cerebellum in a sex-dependent fashion. Furthermore, perinatal low-dose THC recapitulates these findings. We hypothesize that proper granule cell CB1 function is necessary for the appropriate maturation of granule cells. As a corollary, we also hypothesize that disruption of this CB1 receptor signaling (for example, by THC) impairs cerebellar development, increasing an individual's risk for psychiatric disease. In the following R21 proposal we will test the hypothesis that CB1 receptors play a significant role in cerebellar development by completing the following three aims.
Aim 1. Characterize expression and developmental requirements of CB receptors and associated components of the eCB signaling machinery during postnatal cerebellar development. Using well- characterized antibodies, expression of CB1 and the enzymes synthesizing and degrading endocannabinoids in the developing cerebellum will be localized in time and space.
Aim 2. How does exposure to exogenous cannabinoids affect cerebellar development? Expanding on our preliminary results, the role of CB1 receptors in modulating cerebellar development and granule cell maturation following THC exposure will be investigated.
Aim 3. Assess the role of CB signaling in the GC proliferation to differentiation switch. Following up on preliminary studies, we will determine if THC treatment affects the switch of granule cells from proliferation to differentiation, as a likely mechanism for THC impairment of cerebellar development. Together, the results of these studies will define the role of CB1 receptors in the cerebellar foliation in a sex- specific fashion and determine if perinatal cannabis (as modeled by THC administration) affects this process.

Public Health Relevance

The widespread use cannabis by women of child-bearing age is a major public health concern in the US as heavy prenatal cannabis exposure is associated with detrimental psychological outcomes. The work proposed here uses a multidisciplinary approach to explore the role of endogenous cannabinoids in development of the cerebellum and how THC exposure during critical periods of cerebellar development may affect its development. Understanding these mechanisms and THC's interaction with them is necessary for the development of therapies, effective prevention programs and to inform decisions on public policies including cannabis legalization and access.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Wu, Da-Yu
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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