In many synapses, bursts of high-frequency activity cause a progressive reduction of the postsynaptic response. This phenomenon of use-dependent short-term plasticity (STP), termed short-term synaptic depression CX-5461 concentration (STD), is observed at a variety of synapse types, including glutamatergic hippocampal and cortical synapses, climbing fiber synapses in the cerebellum, or the calyx of Held synapse (Dittman and Regehr, 1998; Stevens and Wesseling, 1998; Wang and Kaczmarek, 1998; Zucker and Regehr, 2002). STP and the recovery from STD
play a key role in determining the signaling capacity and processing speed of neuronal networks, and have been implicated in many brain processes, such as cortical gain control (Abbott et al., 1997), working memory (Mongillo et al., 2008), motor control (Nadim and Manor, 2000), sensory adaptation (Chung et al., 2002), and sound localization (Cook et al., 2003). A major cause of STD in hippocampal neurons (Rosenmund and Stevens, 1996) and the calyx of Held (von Gersdorff et al., 1997; Weis et al., 1999;
Wu and Borst, 1999) is the progressive exhaustion of the readily releasable pool (RRP) of fusion competent synaptic vesicles (SVs) during high-frequency activity, until a steady state is reached where SV fusion and replenishment are balanced (Neher and Sakaba, 2008; Zucker and Regehr, 2002). The replenishment rate of releasable SVs is augmented during and after high-frequency action potential Akt inhibitor (AP) firing—up to 30-fold in some synapse types—and considerable evidence indicates that this occurs in response to the elevation of the presynaptic calcium concentration [Ca2+]i (Dittman and Regehr, 1998; Sakaba and Neher, 2001; Stevens and Wesseling, 1998; Wang and Kaczmarek, 1998).
Residual presynaptic [Ca2+]i accelerates the recovery from STD by activating the molecular machinery that mediates RRP refilling, and in hippocampal neurons and the calyx of Held the Ca2+-sensing protein Calmodulin (CaM) is thought to be a key component of this machinery (Junge et al., 2004; Sakaba and Neher, 2001). The size of the RRP at rest and its replenishment during and after depletion are critically dependent on SV priming, a key process in the SV cycle that generates fusion competent SVs. In mammals, the active zone (AZ) proteins Munc13-1, bMunc13-2, ubMunc13-2, Vasopressin Receptor and Munc13-3 are essential priming factors. No RRP is generated and spontaneous and evoked SV fusions are completely abolished upon genetic ablation of Munc13s in hippocampal neurons (Varoqueaux et al., 2002). Furthermore, the SV priming activity of Munc13s is a critical determinant of STP characteristics. Munc13-1 expressing hippocampal neurons in autaptic culture exhibit STD, whereas neurons expressing ubMunc13-2, bMunc13-2, or Munc13-3 exhibit short-term enhancement (STE) of the synaptic response (Lipstein et al., 2012; Rosenmund et al., 2002).