Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor.

In utero exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Delta(9)-THC-induced cognitive impairments, the neuronal basis of Delta(9)-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB(1) cannabinoid receptor (CB(1)R) on cholecystokinin-expressing interneurons induces chemotaxis that is additive with brain-derived neurotrophic factor (BDNF)-induced interneuron migration. We find that Src kinase-dependent TrkB receptor transactivation mediates endocannabinoid (eCB)-induced chemotaxis in the absence of BDNF. Simultaneously, eCBs suppress the BDNF-dependent morphogenesis of interneurons, and this suppression is abolished by Src kinase inhibition in vitro. Because sustained prenatal Delta(9)-THC stimulation of CB(1)Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB(1)R activity governs proper interneuron placement and integration during corticogenesis. Moreover, eCBs use TrkB receptor-dependent signaling pathways to regulate subtype-selective interneuron migration and specification.

[1]  Prahlad T. Ram,et al.  The Gαo/i-coupled Cannabinoid Receptor-mediated Neurite Outgrowth Involves Rap Regulation of Src and Stat3* , 2005, Journal of Biological Chemistry.

[2]  Y. Ben-Ari,et al.  Altering cannabinoid signaling during development disrupts neuronal activity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[3]  A. Finazzi-Agro’,et al.  Lipid Rafts Control Signaling of Type-1 Cannabinoid Receptors in Neuronal Cells , 2005, Journal of Biological Chemistry.

[4]  S. Hestrin,et al.  Electrical Coupling among Irregular-Spiking GABAergic Interneurons Expressing Cannabinoid Receptors , 2004, The Journal of Neuroscience.

[5]  G. Schulte,et al.  Brain‐derived neurotrophic factor controls functional differentiation and microcircuit formation of selectively isolated fast‐spiking GABAergic interneurons , 2004, The European journal of neuroscience.

[6]  F. Lee,et al.  Transactivation of Trk Neurotrophin Receptors by G-Protein-Coupled Receptor Ligands Occurs on Intracellular Membranes , 2004, The Journal of Neuroscience.

[7]  D. Fortin,et al.  Endocannabinoid signalling selectively targets perisomatic inhibitory inputs to pyramidal neurones in juvenile mouse neocortex , 2004, The Journal of physiology.

[8]  A. Ullrich,et al.  Cannabinoids Induce Cancer Cell Proliferation via Tumor Necrosis Factor α-Converting Enzyme (TACE/ADAM17)-Mediated Transactivation of the Epidermal Growth Factor Receptor , 2004, Cancer Research.

[9]  S. Pyne,et al.  Receptor tyrosine kinase-GPCR signal complexes. , 2003, Biochemical Society transactions.

[10]  Gareth Williams,et al.  Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain , 2003, The Journal of cell biology.

[11]  Elaine Fuchs,et al.  Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  T. Freund,et al.  Postnatal development and migration of cholecystokinin-immunoreactive interneurons in rat hippocampus , 2003, Neuroscience.

[13]  Y. Morozov,et al.  Post‐natal development of type 1 cannabinoid receptor immunoreactivity in the rat hippocampus , 2003, The European journal of neuroscience.

[14]  T. Freund,et al.  Role of endogenous cannabinoids in synaptic signaling. , 2003, Physiological reviews.

[15]  G. Paratcha,et al.  The Neural Cell Adhesion Molecule NCAM Is an Alternative Signaling Receptor for GDNF Family Ligands , 2003, Cell.

[16]  S. Anderson,et al.  Cortical interneuron fate determination: diverse sources for distinct subtypes? , 2003, Cerebral cortex.

[17]  Y. Hurd,et al.  Preferential limbic expression of the cannabinoid receptor mRNA in the human fetal brain , 2003, Neuroscience.

[18]  Á. Pazos,et al.  Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain , 2003, The European journal of neuroscience.

[19]  L. Ferraro,et al.  Prenatal exposure to a cannabinoid agonist produces memory deficits linked to dysfunction in hippocampal long-term potentiation and glutamate release , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  F. Walsh,et al.  The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response , 2003, The Journal of cell biology.

[21]  K. Mackie,et al.  Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration , 2003, The Journal of Neuroscience.

[22]  I. Galve-Roperh,et al.  The Endocannabinoid Anandamide Inhibits Neuronal Progenitor Cell Differentiation through Attenuation of the Rap1/B-Raf/ERK Pathway* , 2002, The Journal of Biological Chemistry.

[23]  H. Jahnsen,et al.  Pilocarpine-induced seizure-like activity with increased BNDF and neuropeptide Y expression in organotypic hippocampal slice cultures , 2002, Brain Research.

[24]  R. Nicoll,et al.  Endocannabinoid Signaling in the Brain , 2002, Science.

[25]  F. Lee,et al.  Activation of Trk Neurotrophin Receptor Signaling by Pituitary Adenylate Cyclase-activating Polypeptides* , 2002, The Journal of Biological Chemistry.

[26]  A. Patapoutian,et al.  Trk receptors: mediators of neurotrophin action , 2001, Current Opinion in Neurobiology.

[27]  S. Thayer,et al.  Cannabinoids Inhibit the Formation of New Synapses between Hippocampal Neurons in Culture , 2001, The Journal of Neuroscience.

[28]  G. Marsicano,et al.  Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain , 1999, The European journal of neuroscience.

[29]  Ken Mackie,et al.  Presynaptically Located CB1 Cannabinoid Receptors Regulate GABA Release from Axon Terminals of Specific Hippocampal Interneurons , 1999, The Journal of Neuroscience.

[30]  P. Fried,et al.  Differential effects on cognitive functioning in 13- to 16-year-olds prenatally exposed to cigarettes and marihuana. , 1998, Neurotoxicology and teratology.

[31]  R. McKay,et al.  Neurotrophins Stimulate Chemotaxis of Embryonic Cortical Neurons , 1997, The European journal of neuroscience.

[32]  Leyuan Shi,et al.  Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. , 1997, Science.

[33]  H. Thoenen,et al.  GABAergic Stimulation Regulates the Phenotype of Hippocampal Interneurons through the Regulation of Brain-Derived Neurotrophic Factor , 1996, Neuron.

[34]  A. Ullrich,et al.  Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors , 1996, Nature.

[35]  P. Lönnerberg,et al.  Role of variable beta-hairpin loop in determining biological specificities in neurotrophin family. , 1994, The Journal of biological chemistry.

[36]  D. Sternberg,et al.  K-252a inhibits nerve growth factor-induced trk proto-oncogene tyrosine phosphorylation and kinase activity. , 1992, The Journal of biological chemistry.

[37]  Franjo Grotenhermen,et al.  Pharmacokinetics and Pharmacodynamics of Cannabinoids , 2003, Clinical pharmacokinetics.