Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

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Abstract
In utero exposure to Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Δ 9 -THC-induced cognitive impairments, the neuronal basis of Δ 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 Δ 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.