Abstract
In contrast to the adult brain, the adult spinal cord is a non-neurogenic environment. Understanding how to manipulate the spinal cord environment to promote the formation of new neurons is an attractive therapeutic strategy for spinal cord injury and disease. The cannabinoid 1 receptor (CB1R) has been implicated as a modulator of neural progenitor cell proliferation and fate specification in the brain; however, no evidence exists for modulation of adult spinal cord progenitor cells. Using adult rat spinal cord primary cultures, we demonstrated that CB1R antagonism with AM251 significantly decreased the number of Nestin(+) cells, and increased the number of βIII tubulin(+) and DCX(+) cells, indicative of neuronal differentiation. AM251’s effect was blocked by co-application of the CB1R agonists, WIN 55, 212-2, or ACEA. Consistent with our hypothesis, cultures, and spinal cord slices derived from CB1R knock-out (CB1−/−) mice had significantly higher levels of DCX(+) cells compared to those derived from wild type (CB1+/+) mice, indicative of enhanced neuronal differentiation in CB1−/− spinal cords. Moreover, AM251 promoted neuronal differentiation in CB1+/+, but not in CB1−/− cultures. Since CB1R modulates synaptic transmission, and synaptic transmission has been shown to influence progenitor cell fate, we evaluated whether AM251-induced neuronal differentiation was affected by chronic inactivity. Either the presence of the voltage-dependent sodium channel blocker tetrodotoxin (TTX), or the removal of mature neurons, inhibited the AM251-induced increase in DCX(+) cells. In summary, antagonism or absence of CB1R promotes neuronal differentiation in adult spinal cords, and this action appears to require TTX-sensitive neuronal activity. Our data suggest that the previously detected elevated levels of endocannabinoids in the injured adult spinal cord could contribute to the non-neurogenic environment and CB1R antagonists could potentially be used to enhance replacement of damaged neurons.
Highlights
The cannabinoid 1 receptor (CB1R) is a G-protein coupled receptor originally discovered as the specific binding cite of the major psychoactive constituent of marijuana
CB1R IS PRESENT ON VARIOUS ADULT SPINAL CORD CELLS, INCLUDING PROGENITORS Because the goal was to determine the role that CB1R plays in modulating the fate of the progenitors, the presence of the receptor was determined in our two cell populations of interest: neural progenitors and immature neurons
The neurogenic response elicited by AM251 was blocked by the presence of the CB1R agonists WIN 55, 212-2, or ACEA, and of TTX
Summary
The cannabinoid 1 receptor (CB1R) is a G-protein coupled receptor originally discovered as the specific binding cite of the major psychoactive constituent of marijuana (cannabis). CB1R is involved in developmental processes such as proliferation, survival, and differentiation of neural progenitor cells derived from embryonic and adult rodent brain (Wilson and Nicoll, 2002). Though these studies demonstrate the importance of CB1R in adult brain neurogenesis, controversy exists regarding whether activation or inhibition of CB1R induces neuronal differentiation of brain progenitor cells (Rueda et al, 2002; Hill et al, 2006; Aguado et al, 2007). The ability to direct the progenitors to a neuronal fate by manipulating the non-permissive adult spinal www.frontiersin.org
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