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.
Berghuis
Paul
P
Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Scheeles väg 1:A1, Karolinska Institutet, S-17177 Stockholm, Sweden.
Dobszay
Marton B
MB
Wang
Xinyu
X
Spano
Sabrina
S
Ledda
Fernanda
F
Sousa
Kyle M
KM
Schulte
Gunnar
G
Ernfors
Patrik
P
Mackie
Ken
K
Paratcha
Gustavo
G
Hurd
Yasmin L
YL
Harkany
Tibor
T
D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D002454:Cell Differentiation; D002465:Cell Movement; D002540:Cerebral Cortex / Q000187:drug effects* / Q000196:embryology; D002633:Chemotaxis; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D063388:Endocannabinoids; D006624:Hippocampus / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D007395:Interneurons / Q000378:metabolism*; D009024:Morphogenesis; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism*; D043882:Receptors, Cannabinoid / Q000378:metabolism; D011955:Receptors, Drug / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019966:Substance-Related Disorders; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D005680:gamma-Aminobutyric Acid; D020813:Receptor, trkB; D019061:src-Family Kinases