The functional defects described above were observed as early as P16-20, CHIR-99021 mw the age window when nerve terminal degeneration is likely to begin in CSPα KO mice, suggesting that the functional

defects may not be secondary to nerve terminal degeneration. In summary, Rozas et al. (2012) and Zhang et al. (2012) have discovered a regulatory role of CSPα in dynamin 1-mediated synaptic vesicle endocytosis and recycling (Figure 1). Their findings advance our understanding of the molecular mechanisms regulating synaptic transmission and may shed light on the study of synapse loss during neurodegeneration. As a new member involved in regulating endocytosis, CSPα binds directly to dynamin 1 and facilitates dynamin 1 polymerization, a conformation critical in mediating vesicle fission (Figure 1). This mechanism may not only explain the endocytosis defect in CSPα KO mice but also contribute to the observed defects Docetaxel mouse in exocytosis. Recent studies have shown that blocking endocytosis inhibits vesicle mobilization to the readily releasable pool, likely via inhibition of the clearance of the recently exocytosed proteins from the release site (Wu et al., 2009 and Hosoi et al., 2009). Consequently, defects in vesicle priming observed in CSPα KO mice may be due to the endocytosis defect (Figure 1). Like many pioneering studies, the studies by Rozas et al.

(2012) and Zhang et al. (2012) raise many important questions and unsettled issues. For example, we do not know how CSPα facilitates dynamin 1 polymerization. The form of endocytosis regulated by CSPα also remains unclear, considering that there are at least three forms of endocytosis: the classical clathrin-dependent slow endocytosis, rapid, clathrin-independent endocytosis, and bulk endocytosis that generates large endosome-like structures (Wu et al., 2007). Although impaired dynamin 1 polymerization seems the obvious cause of inhibition in endocytosis, whether it is also

responsible for the decrease in the recycling pool and the difficulty in rereleasing recently endocytosed vesicles in CSPα KO mice is unclear. The evidence supporting a defect in vesicle priming in CSPα KO mice is indirect. Direct evidence showing a decrease in the docked vesicle number, the readily releasable vesicle pool Isotretinoin size, and/or the rate of vesicle mobilization to the readily releasable pool awaits further study. It also remains untested whether the defects in dynamin 1 polymerization and vesicle recycling cause synapse loss. This possibility has been challenged by a recent study showing that SNAP-25 overexpression is sufficient to rescue synapse loss and degeneration in cultured neurons derived from CSPα KO mice (Sharma et al., 2011a). In addition to SNAP-25 and dynamin 1, there are around 20 other proteins that are reduced in CSPα KO mice (Zhang et al., 2012).