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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Wu, Da-Yu
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
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Alpár, Alán; Tortoriello, Giuseppe; Calvigioni, Daniela et al. (2014) Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nat Commun 5:4421
Tortoriello, Giuseppe; Morris, Claudia V; Alpar, Alan et al. (2014) Miswiring the brain: ?9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. EMBO J 33:668-85
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Malenczyk, Katarzyna; Jazurek, Magdalena; Keimpema, Erik et al. (2013) CB1 cannabinoid receptors couple to focal adhesion kinase to control insulin release. J Biol Chem 288:32685-99
Keimpema, Erik; Tortoriello, Giuseppe; Alpar, Alan et al. (2013) Nerve growth factor scales endocannabinoid signaling by regulating monoacylglycerol lipase turnover in developing cholinergic neurons. Proc Natl Acad Sci U S A 110:1935-40
Tortoriello, Giuseppe; Rhodes, Brandon P; Takacs, Sara M et al. (2013) Targeted lipidomics in Drosophila melanogaster identifies novel 2-monoacylglycerols and N-acyl amides. PLoS One 8:e67865
Antonucci, Flavia; Alpar, Alan; Kacza, Johannes et al. (2012) Cracking down on inhibition: selective removal of GABAergic interneurons from hippocampal networks. J Neurosci 32:1989-2001
Attems, Johannes; Alpar, Alan; Spence, Lauren et al. (2012) Clusters of secretagogin-expressing neurons in the aged human olfactory tract lack terminal differentiation. Proc Natl Acad Sci U S A 109:6259-64
Alpar, Alan; Attems, Johannes; Mulder, Jan et al. (2012) The renaissance of Ca2+-binding proteins in the nervous system: secretagogin takes center stage. Cell Signal 24:378-87

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