The neuronal basis of cannabis-induced developmental deficits in the CNS

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DESCRIPTION (provided by applicant): The endocannabinoid system has recently been established as a major feedback circuitry controlling synaptic plasticity at multiple neurochemically distinct synapse populations in the meosocorticolimbic system of the adult. However, the functions of endocannabinoid signaling during patterning of the central nervous system, in particular instructing the migration and phenotypic morphometric differentiation of neuronal precursors, in the embryonic brain are unknown. Our lack of knowledge on the cellular specification of endocannabinoid signaling during brain development is surprising given that cannabinoid receptors are the preferred cellular targets of 9-tetrahydrocannabinol (THC), the active component from cannabis, and cannabis smoking during pregnancy causes life-long motor and cognitive deficits, controlled centrally by mesocorticolimbic neuronal circuitries, in the affected offspring. We have previously found that CB1 cannabinoid receptors are selectively localized to the limbic system of the human embryo as early as week 14 of gestation, endocannabinoids and phytocannabinoids are instructive for neuronal migration and cortical interneuron specification, and identified endocannabinoids as a novel class of repulsive axon guidance cues for GABAergic interneurons. In the present project we will focus on: (1) defining the cellular consequences of THC exposure during critical periods of neuronal precursor migration and neuronal synaptogenesis with particular emphasis on their association with GABAergic and dopaminergic (DAergic) neurons in the mesocorticolimbic system and (2) identifying cellular regulatory mechanisms on the transcriptome level that are relevant to THC-induced developmental changes. An integrative, multidiscplinary series of studies will be performed in green fluorescent protein-expressing reporter mice that allow selective visualization of genetically-tagged target neurons. Subsequently, transcriptome analysis from animal model studies of prenatal THC administration will be combined with identifying developmentally-regulated gene sets in mesocorticolimbic neurons whose expression is differentially regulated by prenatal THC in a unique material of cannabis-exposed human fetal brain specimens. Expanding our knowledge of the basic developmental and signaling principles controlled by the endocannabinoid system will provide significant insights about pathological mechanisms of prenatal cannabis exposure that is of significant concern in society considering the continued frequent use of marijuana by pregnant women. The results of this project will expand our current understanding of the functional significance of the endogenous cannabinoid signaling system during brain development and the pathological mechanisms associated with prenatal cannabis exposure. Such insights are of significant importance considering that marijuana is the most commonly used illicit drug by pregnant women and young women of childbearing age.