Clearly, the question of the in vivo role of inhibition in the MSO has not been fully answered. The second study in this issue (Roberts et al., 2013) provides new

insight into the role that inhibition may play in the MSO. Roberts and colleagues developed a new thick slice preparation that includes the whole macrocircuit shown in Figure 1A, except for the cochlea. They were thus able to stimulate the auditory nerve and obtain IPSP and EPSP recordings from the MSO cells. This is the first time that IPSPs evoked by auditory nerve stimulation have been obtained from MSO neurons in brain slices. Vismodegib mouse Surprisingly, they found that stimulating the inhibitory inputs from the LNTB and MNTB caused IPSPs in MSO neurons 300–400 μs prior to excitation, even though these pathways involve an extra synapse. They suggest that all the inhibitory sources of input to the MSO provide feed-forward inhibition that restricts the

MSO neuron from firing except when the binaural excitatory inputs provide the largest, most synchronous EPSPs. In contrast to the in vivo experiments that blocked inhibition (Pecka et al., 2008), Roberts et al. (2013) did not find that the presence Y-27632 solubility dmso of inhibition shifted the location of the ITD function. Furthermore, both studies in this issue provide a case study of how to achieve linear synaptic integration using cellular mechanisms, like inhibitory synaptic conductances and potassium channel gating, that are individually nonlinear. What are the biophysical mechanisms that allow coincidence detection à la Jeffress to occur? In the barn owls, recent tour de force in vivo recordings have Adenosine shown that NL (the bird analog of the MSO) neurons have remarkable properties: (1) a very low input resistance and a passive soma that is devoid of Na+ channels, (2) insanely fast EPSCs (half-width of 100 μs; perhaps due to higher bird-brain temperatures of 40°C–41°C), and (3) hundreds of phase-locked synaptic inputs from the contra and ipsilateral afferent

axons (analogs of the SBC axons shown in Figure 1A; Funabiki et al., 2011). This allows the bird’s NL neurons to function as leaky coincidence detectors that produce phase-locked spikes to sound frequencies of up to 8 kHz (Köppl, 2012). In mammals, phase locking can occur only for frequencies < 2–3 kHz. Like NL neurons, MSO neurons are very leaky (input resistance of 5–10 MΩ) and have small spikes (about 10–30 mV in amplitude), but unlike NL neurons they receive surprisingly few excitatory inputs from SBC axons (2–4 large excitatory fibers per dendrite) and do not appear to have ultrafast EPSCs (Couchman et al., 2010). The role of inhibition in these two circuits is also very different (see Roberts et al., 2013). Thus, the biophysical mechanisms for coding low frequency sounds appear to be very different in birds and small-headed mammals.