, 1994, Yoshihara and Littleton, 2002, Maximov and Südhof, 2005 and Sun et al., 2007). In most synapses, the remaining Ca2+-stimulated release is dramatically facilitated during action-potential bursts in vitro and in vivo ( Xu et al., 2012). This remaining release is often referred to as “asynchronous” because it lags after synchronous release and is not

tightly coupled to an action potential. Asynchronous release exhibits distinct properties in different types of neurons and probably comprises multiple processes. Hippocampal Syt1 knockout neurons exhibit significant asynchronous release that is amplified by facilitation during action-potential trains (Maximov and Südhof, 2005), so much so that the total amount of asynchronous release Selisistat supplier in Syt1 knockout neurons becomes identical to that observed in wild-type neurons (Yoshihara and Littleton, 2002, Nishiki Sorafenib concentration and Augustine, 2004, Maximov and Südhof, 2005 and Xu et al., 2012)! In contrast, Syt2 knockout synapses in the calyx of Held display relatively little asynchronous release, which exhibits only modest facilitation during high-frequency stimulus trains (Sun et al., 2007). In yet another example for a difference between synapses, some neurons such as

cholecystokinin-containing interneurons in the hippocampus use a facilitating type of asynchronous release as the dominant form of release even in wild-type conditions (Hefft and Jonas, 2005, Daw et al., 2009 and Karson et al., 2009). These observations prompted the question, what is asynchronous release, and what Ca2+ sensor mediates asynchronous release? Studies in chromaffin cells provided the first clue to

answering these questions. Earlier experiments had shown that deletion of Syt1 in chromaffin cells produced a small but significant decrease in Ca2+-stimulated exocytosis and a delay in the rate of exocytosis (Sørensen et al., 2003). In a pivotal study, Schonn et al. (2008) almost then demonstrated that deletion of only Syt7, a Ca2+-binding synaptotagmin that had previously been implicated as a Ca2+ sensor in exocytosis in PC12 cells (Sugita et al., 2001 and Fukuda et al., 2004), also produced a relatively small decrease in Ca2+-stimulated exocytosis in chromaffin cells. However, the double deletion of both Syt1 and Syt7 caused a dramatic ablation of nearly all Ca2+-induced exocytosis (Schonn et al., 2008). This finding suggested that at least in chromaffin cells, Syt1 and Syt7 are redundant Ca2+ sensors for exocytosis with distinct response kinetics. Syt7 is also expressed at high levels in brain—even higher than Syt1—and is localized to synapses (Sugita et al., 2001). However, initial attempts to uncover a role for Syt7 in synaptic exocytosis using constitutive Syt1 and Syt7 knockout mice were disappointingly unsuccessful (Maximov et al., 2009).