Loss of Cannabinoid CB 1 Receptors Induces Cortical Migration Malformations and Increases Seizure Susceptibility

Abstract

Neuronal migration is a fundamental process of brain development, and its disruption underlies devastating neurodevelopmental disorders. The transcriptional programs governing this process are relatively well characterized. However, how environmental cues instruct neuronal migration remains poorly understood. Here, we demonstrate that the cannabinoid CB₁ receptor is strictly required for appropriate pyramidal neuron migration in the developing cortex. Acute silencing of the CB₁ receptor alters neuronal morphology and impairs radial migration. Consequently, CB₁ siRNA-electroporated mice display cortical malformations mimicking subcortical band heterotopias and increased seizure susceptibility in adulthood. Importantly, rescuing the CB₁ deficiency-induced radial migration arrest by knockdown of the GTPase protein RhoA restored the hyperexcitable neuronal network and seizure susceptibility. Our findings show that CB₁ receptor/RhoA signaling regulates pyramidal neuron migration, and that deficient CB₁ receptor signaling may contribute to cortical development malformations leading to refractory epilepsy independently of its canonical neuromodulatory role in the adult brain.

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