V.S. and M.S.), the Gatsby Charitable Foundation (M.S.), and the following awards to K.V.S.: NIH Director’s Pioneer Award (1DP10D006409), the Burroughs Wellcome Fund Career Award in the Biomedical Sciences, the Center for Integrated Systems at Stanford, the NSF Center for Neuromorphic Systems Engineering at Caltech, the Sloan Foundation, and the Whitaker Foundation. “
“Neurons are bombarded by ongoing excitatory and inhibitory inputs. What are the mechanisms that allow a neuron to detect the arrival of an

input carrying an important message requiring an immediate specific response? In this issue of Neuron, Kuo and Trussel (2011) reveal a robust mechanism that begins to answer this question CX 5461 by exploring the effects of noradrenaline (NA) on inhibitory inputs at fusiform cells, the principal cells of the mouse dorsal

cochlear nucleus (DCN). Inhibitory inputs in DCN fusiform cells occur as spontaneous IPSCs (sIPSCs) or as feedforward inhibition generated by parallel fiber excitation of cartwheel cells (eIPSCs). Surprisingly, NA dramatically reduced sIPSCs while increasing eIPSCs. Cartwheel cells are the source of both the spontaneous and the evoked IPSCs in fusiform principal cells. Thus, Kuo and Trussell systematically investigated the synaptic mechanisms between cartwheel cells and DCN principal cells to explain the opposing effects of NA. First, they examined the possibility Selumetinib supplier that NA enhances parallel fiber input at cartwheel cells. However, they demonstrated TCL that NA does not affect excitatory postsynaptic (EPSC) inputs in cartwheel cells. Next, they examined whether cartwheel connection with fusiform cells is modulated by NA. Paired recordings between presynaptic cartwheel cell and postsynaptic fusiform cells indicated that this synapse is also insensitive to NA. They further showed that changes in the membrane potential of cartwheel cells do not affect sIPSCs in fusiform cells. Thus, NA does not appear to act via its conventional presynaptic mechanisms (Berridge and Waterhouse, 2003 and Waterhouse and

Woodward, 1980). Next, they considered the possible impact of NA on spontaneous spiking of cartwheel cells. They first showed that cartwheel to fusiform cells exhibit activity-dependent synaptic depression. Further using paired recordings, they showed that the recovery from synaptic depression is slow (time constants of 5–6 s). Given that cartwheel cells exhibit spiking at about 8–13 Hz (Davis and Young, 1997 and Golding and Oertel, 1997), their synapses are not allowed to recover and exhibit ongoing depression. Thus, spontaneous spiking in cartwheel cells has two consequences. First, this activity generates sIPSCs in their postsynaptic cells, i.e., fusiform cells, and second, this ongoing spiking activity generates persistent synaptic depression. Using cell-attached recording, Kuo and Trussell showed that the spontaneous spiking of cartwheel cells is silenced by application of NA.