Furthermore, once produced, how far do eCBs diffuse? While AEA seems to be transported by a lipid carrier protein, whether 2-AG is also transported by a lipid chaperone is unknown. Alternatively, specialized protein/lipid bridges, akin to synaptic intercellular adhesion molecules, could adopt a structural conformation that exposes lipophilic
patches to reduce the retrograde energy barrier. Regardless of the exact mechanism, S3I-201 mouse it is clear that eCB signaling powerfully regulates synaptic function. Developing new technologies to image lipid signaling, in real time, should dramatically propel the field of eCB research forward. Apart from their more traditional role in retrograde signaling, eCBs also appear to act in a nonretrograde manner to modulate postsynaptic function as well as trigger gliotransmission. However, the general physiological
relevance of nonretrograde signaling mediated by TRPV1 in the CNS is not yet clear. While experimental evidence for eCBs targeting postsynaptic receptors is growing, whether presynaptically produced eCBs activate presynaptic CB1Rs or TRPV1 channels to modulate synaptic function remains unknown. In addition, the role of CB1Rs in regulating gliotransmission and, indirectly, synaptic plasticity warrants further investigation. Given the myriad of evidence supporting synaptic CB1Rs in modulating synaptic transmission, the precise conditions necessary for activating neuronal versus astrocytic CB1Rs must be defined. Several other fundamental mechanistic
questions remain unanswered. What are the rules governing CB1R Selleck Pazopanib these trafficking into and out of membranes? What are the conditions required for CB1R heteromerization with other neuromodulatory receptors, and what is their impact on synaptic function? As for the two main eCBs, 2-AG and AEA, are there specific patterns of activity that predominantly mobilize one lipid versus the other? Perhaps these eCBs subserve specific functions at the synapse. If so, which ones? What is the precise role of tonic eCB release in the brain? In vitro approaches are unquestionably useful for addressing fundamental mechanisms underlying synaptic eCB signaling, but much more work in vivo is required to determine their contribution to physiological and pathological conditions. While a great deal of progress has been made in our understanding of eCB signaling and synaptic function, the greatest challenges lie ahead. This work was supported by the NIH (R01-MH081935 and R01-DA17392 to P.E.C). A.E.C. was supported by a Ruth L. Kirschstein Award from the U.S. National Institute of Neurological Disorders and Stroke (F32-NS071821). Y.H. was supported by the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad. We apologize to authors whose work we could not cite due to space limitations. “
“Neuropeptides offer useful entry points to study how the brain controls behavior.
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