title: A Role for the Cannabinoid 1 Receptor in Neuronal Differentiation of Adult Spinal Cord Progenitors in vitro is Revealed through Pharmacological Inhibition and Genetic Deletion.
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.
authors.affiliation: Department of Anesthesiology, New York University Langone Medical Center New York, NY, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Sideris
authors.forename: Tatiana
authors.initials: T
authors.lastname: Bekker
authors.forename: Wai Si
authors.initials: WS
authors.lastname: Chan
authors.forename: Jose V
authors.initials: JV
authors.lastname: Montoya-Gacharna
authors.forename: Thomas J J
authors.initials: TJ
authors.lastname: Blanck
authors.forename: Esperanza
authors.initials: E
authors.lastname: Recio-Pinto