For the majority of axons in the CNS that release neuropeptides, I favor a third local diffusion hypothesis- that neuropeptides released by most neurons act locally on

cells near the release site, with a distance of action of a few microns. Thus, a peptide’s action would be on its synaptic partners (even if the peptide is not released at the presynaptic specialization) and on immediately adjacent cells. In part this perspective is based on the low frequency of dense core vesicles in most CNS axons and the hours it would take to replenish released peptides from sites of synthesis in the cell body, making it difficult to achieve a substantial extracellular concentration of neuropeptide needed for a long-distance effect. In this context, the relatively slow replenishment of neuropeptide modulators may differ from catecholamine neuromodulators BMN 673 cell line that can be synthesized rapidly within axon terminals to support ongoing release. Furthermore,

as determined with ultrastructural analysis, a complex system of astrocytic processes surrounds many axodendritic synaptic complexes and tends to attenuate long-distance transmitter diffusion from many release sites ( Figure 1; Peters et al., 1991), thereby impeding actions of peptides at far-away targets, and maintaining a higher local extracellular concentration of the peptide. Peters et al. credit Ramon y Cajal with favoring the concept that a central function for glia was isolation of neuronal microdomains. That peptides released by most neurons may act within a few microns of the release site does not negate the fact GS-1101 clinical trial that some peptides can be released in large quantities and can act at longer distances. This may be the exception rather than the rule. For instance, considering the multiple subtypes of highly specialized NPY or somatostatin interneurons second in the hippocampus or cortex, coupled with the multiple peptide responses reported in nearby cells and the highly specialized functions of different nearby interneurons, often with restricted functional

microdomains (Freund and Buzsáki, 1996; Bacci et al., 2002; Klausberger et al., 2003), it seems most likely that released peptides here act primarily on nearby receptive partners. Consistent with the local diffusion perspective are findings related to peptides such as pigment dispersing factor (PDF) which plays a key role in regulating circadian rhythms of invertebrates (Im and Taghert, 2010; Zhang et al., 2010). Although cells that release PDF project to several regions of the Drosophila brain, the response of the releasing cells to PDF appears to be critical for some aspects of circadian function. Secreted PDF acts on PDF autoreceptors expressed by the releasing lateral-ventral pacemaker neurons to regulate the time of day during which behavioral activity occurs ( Choi et al., 2012; Taghert and Nitabach, 2012, this issue of Neuron). Most neuropeptides act by binding to a seven-transmembrane domain G protein-coupled receptor (GPCR).