Loss of Cannabinoid CB₁Receptors 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.

Interference with the Cannabinoid Receptor CB1R Results in Miswiring of GnRH3 and AgRP1 Axons in Zebrafish Embryos

“…Alternatively, CB1R could be involved in the timing of GnRH3 neuronal migration. A role of CB1R in neuronal migration has been previously reported during radial migration of immature pyramidal neurons in the cortex [23,72], and eCB signaling has been shown to promote migration of newborn neurons along the rostral migratory stream in the postnatal mouse brain [14]. Further experiments are needed to define a possible role of CB1R in GnRH3 neuronal migration.…”

Endocannabinoid Signaling in Embryonic Neuronal Motility and Cell–Cell Contact – Role of mGluR5 and TRPC3 Channels

“…The endocannabinoid system has previously been shown to have an important role in cortical neuronal migration. Interference with endocannabinoid signaling by receptor knock-down or pharmacologic inhibition causes pyramidal cell migration defects and cortical malformations (Mulder et al, 2008;Saez et al, 2014;Diaz-Alonso et al, 2017). Migratory defects have also been seen upon knocking down or pharmacologically blocking of DAGL or MAGL (reviewed in Maccarrone et al, 2014).…”

“…In addition to the central role in postnatal precursor cell motility (Oudin et al, 2011a,b), interference with eCBs signaling have been shown to cause pyramidal cell migration defects and cortical malformations (Mulder et al, 2008;Saez et al, 2014;Diaz-Alonso et al, 2017). The aim of the present study was thus to study the role of the 2-AG in the regulation of the motility pattern of cortical embryonic neuroblasts, and the interaction the between mGluR5/TRPC3 and eCB systems.…”

Synthetic cannabinoids and their impact on neurodevelopmental processes

“…Furthermore, Díaz‐Alonso et al evidenced the key role of the ECS in promoting a correct neuronal migration. The authors noted that acute silencing of the CB 1 R impaired radial migration and altered neuronal morphology in mice …”