Abstract
Endocannabinoids are recently recognized regulators of brain development, but molecular effectors downstream of type-1 cannabinoid receptor (CB1R)-activation remain incompletely understood. We report atypical coupling of neuronal CB1Rs, after activation by endo- or exocannabinoids such as the marijuana component ∆(9)-tetrahydrocannabinol, to heterotrimeric G12/G13 proteins that triggers rapid and reversible non-muscle myosin II (NM II) dependent contraction of the actomyosin cytoskeleton, through a Rho-GTPase and Rho-associated kinase (ROCK). This induces rapid neuronal remodeling, such as retraction of neurites and axonal growth cones, elevated neuronal rigidity, and reshaping of somatodendritic morphology. Chronic pharmacological inhibition of NM II prevents cannabinoid-induced reduction of dendritic development in vitro and leads, similarly to blockade of endocannabinoid action, to excessive growth of corticofugal axons into the sub-ventricular zone in vivo. Our results suggest that CB1R can rapidly transform the neuronal cytoskeleton through actomyosin contractility, resulting in cellular remodeling events ultimately able to affect the brain architecture and wiring.
Highlights
The morphology of retracted axons was characterized by an F-actin-rich retraction bulb and a thin membranous trailing remnant, the latter of which was not included in the length measurement
Together with our above findings showing that activation of endogenous CB1Rs in organotypic slices leads to non-muscle myosin II (NM II)-dependent arrest or contraction of axonal growth cones, these results suggest that both activation of endogenous CB1Rs and actomyosin contractility are required for correct path finding of corticofugal axons
CB1R acts through heterotrimeric G12/G13 proteins, Rho GTPase, and Rho-associated kinase (ROCK) to induce the contractile interaction of NM II with F-actin
Summary
The endocannabinoid (eCB) system is emerging as an important regulator of brain wiring during development with a variety of functions, ranging from lineage segregation of stem cells to refinement of synaptic functions in complex neuronal networks (Williams et al, 2003; Berghuis et al, 2007; Harkany et al, 2008; Mulder et al, 2008; Vitalis et al, 2008; Watson et al, 2008; Wu et al, 2010).
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