Endocannabinoids regulate interneuron migration and morphogenesis by transactivating the TrkB receptor

In utero exposure to Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the active component from marijuana, induces cognitive deficits enduring into adulthood. Although changes in synaptic structure and plasticity may underlie Δ⁹-THC-induced cognitive impairments, the neuronal basis of Δ⁹-THC-related developmental deficits remains unknown. Using a Boyden chamber assay, we show that agonist stimulation of the CB₁ cannabinoid receptor (CB₁R) 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 Δ⁹-THC stimulation of CB₁Rs selectively increases the density of cholecystokinin-expressing interneurons in the hippocampus in vivo, we conclude that prenatal CB₁R 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.