Control of submillisecond synaptic timing in binaural coincidence detectors by Kv1 channelsRESULTSDISCUSSIONMolecular basis for IK-LVASynaptic sharpening by IK-LVASomato-dendritic distribution of IK-LVAFunctional implications for ITD encoding in vivoMethodsONLINE METHODSSlice preparation.Current-clamp electrophysiology.Analysis.Voltage-clamp electrophysiology.Modeling.AcknowledgmentsAUTHOR CONTRIBUTIONSCOMPETING FINANCIAL INTERESTSReferencesFigure 1 Propagation of simulated EPSPs from the dendrites to the soma in MSO neurons.Figure 2 The shape of EPSPs is stable regardless of propagation distance.Figure 3 A DTX-sensitive conductance mediates EPSP sharpening.Figure 4 Characterization of IK-LVA in outside-out patches.Figure 5 Relative timing of IK-LVA and sEPSPs in whole-cell recordings at 35 °C.Figure 6 VDS for dendritic and somatic EPSC injection in a compartmental model of the MSO.Figure 7 Spatial effects of VDS in anMSO neuron model.Figure 8 Spatio-temporal dynamics of membrane potential and IK-LVA for bilateral ITD-like distal inputs (750 Hz).nature neurOSCIenCe VOLUME 13 | NUMBER 5 | MAY 2010 6 0 1a r t I C l e SThe temporal relationship between excitatory synaptic input and action potential output is critical for sensory encoding as well as for the induction of some forms of synaptic plasticity1,2. However, in the majority of neurons in which excitatory inputs sum in the dendritic arbor, the relative timing of synaptic input is subject to distortions in both time and amplitude as a result of dendritic cable filtering3,4. The computational challenge of maintaining fine temporal resolution in the face of dendritic distortions is especially acute in neurons of the medial superior olive (MSO) in which phase-locked auditory infor-mation from the two ears is first integrated. Principal neurons of the MSO encode microsecond differences in the arrival time of sounds to the two ears (interaural time differences, or ITDs) through systematic variations in the rate of action potential output. Rate-encoded ITDs are a critical cue used by birds and mammals for localizing sounds along the horizontal plane5–7.At the cellular level, discrimination of ITDs in mammals involves the spatial and temporal summation of time-locked glutamatergic excitation and glycinergic inhibition in MSO principal neurons. Excitatory synaptic inputs from spherical bushy cells of the cochlear nucleus are segregated onto different branches of bipolar dendritic arbors8. The axon, where action potential initiation occurs, emerges from the soma or proximal dendrite9,10. Although computational models have been used to predict that this synaptic input segrega-tion in MSO neurons and their avian analogs may improve the fidelity of binaural coincidence detection11–14, there has been almost no experimental data to date regarding the dendritic properties of these cells, and the role of the dendrites in shaping binaural coincidence detection is therefore unclear.To understand how MSO dendrites influence synaptic coinci-dence detection, we combined simultaneous dendritic and somatic current-clamp recordings, both whole-cell and excised patch voltage-clamp recordings, and computational modeling to explore how the properties of MSO dendrites influence binaural coincidence detec-tion and temporal coding. We found that dendritic EPSPs activated a somatically biased population of low voltage–activated K+ channels (KLVA), which accelerated membrane repolarization. The presence of KLVA approximately doubled the temporal resolution of binaural coincidence detection as compared with a passive leak conductance of the same density and imposed a uniform somatic time course of EPSPs propagating from disparate dendritic locations. Thus, both the biophysical properties and spatial distribution of KLVA are critical determinants of the high resolution of binaural coincidence detec-tion in the MSO.RESULTSMSO principal cells were identified in brainstem slices by the bipolar morphology of their dendrites when viewed under infrared differ-ential interference contrast optics9, and by the characteristic onset (single spike) firing pattern and unusually low input resistance these cells exhibit electrophysiologically (average of 12.0 ± 0.69 MΩ for postnatal day 16–19 (P16–19) gerbils, n = 20). To examine how EPSPs are shaped as they propagate from known locations in the dendrites to the soma, we made simultaneous somatic and dendritic current-clamp recordings, injected simulated excitatory postsynaptic cur-rents (sEPSCs, see Online Methods) into the dendrites and varied current amplitude to elicit depolarizations encompassing the entire subthreshold voltage range (Fig. 1a). These simulated EPSPs (sEPSPs) showed marked attenuation following propagation to the soma, which was proportional to the recording distance. In all of the recordings, one of the most notable features of sEPSPs was the voltage dependence 1Section of Neurobiology and Institute for Neuroscience, University of Texas at Austin, Austin, Texas, USA. 2Center for Neural Science, New York University, New York, New York, USA. 3Courant Institute of Mathematical Sciences, New York University, New York, New York, USA. 4These authors contributed equally to this work. Correspondence should be addressed to N.L.G. ([email protected]). Received 15 December 2009; accepted 8 March 2010; published online 4 April 2010; doi:10.1038/nn.2530Control of submillisecond synaptic timing in binaural coincidence detectors by Kv1 channelsPaul J Mathews1,4, Pablo E Jercog2,4, John Rinzel2,3, Luisa L Scott1 & Nace L Golding1Neurons in the medial superior olive process sound-localization cues via binaural coincidence detection, in which excitatory synaptic inputs from each ear are segregated onto different branches of a bipolar dendritic structure and summed at the soma and axon with submillisecond time resolution. Although synaptic timing and dynamics critically shape this computation, synaptic interactions with intrinsic ion channels have received less attention. Using paired somatic and dendritic patch-clamp recordings in gerbil brainstem slices together with compartmental modeling, we found that activation of Kv1 channels by dendritic excitatory postsynaptic potentials (EPSPs) accelerated membrane repolarization in a voltage-dependent manner and actively improved the time resolution of synaptic integration. We found that a somatically biased