Timothy McKinsey for generously sharing the P-S259 class IIa HDAC antibody, and Dr. James Bibb (UTSW) for advice on in vitro Cdk5 assays. We also acknowledge Dr. Eric Olson (UTSW) for sharing HDAC5 KO mice and Yong-Chao Ma (CMRC/Northwestern) for critical reading of the manuscript. L.N.S. was supported by fellowships from NIDA (T32 DA07290 and F32 DA027265) Volasertib in vitro and the FRAXA Foundation. C.W.C. acknowledges the generous support of the Whitehall Foundation, the Simons Foundation (SFARI grant), NIDA (DA008277 and

DA027664), and NEI (EY018207 and a research supplement for underrepresented minorities to M.B.C.). “
“Spontaneous neurotransmitter release is a salient feature of all presynaptic nerve terminals (Fatt and Katz, 1952). Recent studies have shown that these action potential (AP)-independent release events are essential regulators of synaptic homeostasis in terms of both presynaptic release rate and postsynaptic sensitivity (Aoto et al., Carfilzomib mw 2008, Frank et al., 2006, Lee et al., 2010, Sutton et al., 2006 and Sutton et al., 2007). Moreover, there is growing evidence that postsynaptic receptors and signaling elements that respond to spontaneous release events diverge from those that respond to evoked release (Atasoy et al., 2008,

Sara et al., 2011 and Sutton et al., 2007), suggesting a spatial segregation of the two forms of neurotransmission (Zenisek, 2008). Furthermore, a number of studies have provided evidence that presynaptic vesicle populations giving rise to spontaneous release are distinct Phosphoprotein phosphatase from those that

carry out AP-driven neurotransmission (Chung et al., 2010, Fredj and Burrone, 2009, Mathew et al., 2008, Sara et al., 2005 and Virmani et al., 2005). However, this notion remains controversial as some studies have provided contradictory results (Groemer and Klingauf, 2007, Hua et al., 2010 and Wilhelm et al., 2010). In the absence of molecular tags that identify a functionally distinct subpopulation of SVs, it is difficult to ascertain whether these observations disagree in substance or are merely due to vagaries of distinct experimental settings (Chung et al., 2010, Groemer and Klingauf, 2007, Prange and Murphy, 1999 and Sara et al., 2005). Lack of molecular insight into this putative functional heterogeneity also renders the examination of specific signaling consequences of spontaneous release independent of other forms of neurotransmission difficult (Kavalali et al., 2011 and Ramirez and Kavalali, 2011). Synaptobrevin2 (syb2), a key vesicular SNARE essential for all forms of neurotransmission in the CNS, is widely distributed among all vesicle pools as its absence gives rise to deficits in evoked and spontaneous neurotransmission (Schoch et al., 2001).