Hardwiring the Brain: Endocannabinoids Shape Neuronal Connectivity

TLDR

Endocannabinoid signaling roles in CNS development remain unclear. Endocannabinoids trigger CB1 receptor internalization and elimination from filopodia, inducing chemorepulsion and collapse of axonal growth cones in GABAergic interneurons via RhoA activation. CB1 receptors are enriched in axonal growth cones of GABAergic interneurons during late gestation, and endocannabinoids act as axon guidance cues that regulate synaptogenesis and target selection, as shown by impaired target selection in CB1‑deficient interneurons and reduced galvanotropism in Xenopus spinal neurons.

Abstract

The roles of endocannabinoid signaling during central nervous system development are unknown. We report that CB 1 cannabinoid receptors (CB 1 Rs) are enriched in the axonal growth cones of γ-aminobutyric acid–containing (GABAergic) interneurons in the rodent cortex during late gestation. Endocannabinoids trigger CB 1 R internalization and elimination from filopodia and induce chemorepulsion and collapse of axonal growth cones of these GABAergic interneurons by activating RhoA. Similarly, endocannabinoids diminish the galvanotropism of Xenopus laevis spinal neurons. These findings, together with the impaired target selection of cortical GABAergic interneurons lacking CB 1 Rs, identify endocannabinoids as axon guidance cues and demonstrate that endocannabinoid signaling regulates synaptogenesis and target selection in vivo.