In mammals, principal neurons of the medial superior olive (MSO) exhibit biophysical specializations that enable them to detect soundlocalization cues with microsecond precision. In the present study, we used whole-cell patch recordings to examine the development of the intrinsic electrical properties of these neurons in brainstem slices from postnatal day 14 (P14) to P38 gerbils. In the week after hearing onset (P14 -P21), we observed dramatic reductions in somatic EPSP duration, input resistance, and membrane time constant. Surprisingly, somatically recorded action potentials also dramatically declined in amplitude over a similar period (38 Ϯ 3 to 17 Ϯ 2 mV; ϭ 5.2 d). Simultaneous somatic and dendritic patch recordings revealed that these action potentials were initiated in the axon, which primarily emerged from the soma. In older gerbils, the rapid speed of membrane voltage changes and the attenuation of action potential amplitudes were mediated extensively by low voltage-activated potassium channels containing the Kv1.1 subunit. In addition, whole-cell voltage-clamp recordings revealed that these potassium channels increase nearly fourfold from P14 to P23 and are thus a major component of developmental changes in excitability. Finally, the electrophysiological features of principal neurons of the medial nucleus of the trapezoid body did not change after P14, indicating that posthearing regulation of intrinsic membrane properties is not a general feature of all time-coding auditory neurons. We suggest that the striking electrical segregation of the axon from the soma and dendrites of MSO principal neurons minimizes spike-induced distortion of synaptic potentials and thus preserves the accuracy of binaural comparisons.

Neurons in the medial superior olive (MSO) process sound localization cues through binaural coincidence detection, in which excitatory synaptic inputs from each ear are segregated onto different branches of a bipolar dendritic structure and sum at the soma and axon with submillisecond time resolution. Although synaptic timing and dynamics critically shape this remarkable 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 show that activation of Kv1 channels by dendritic EPSPs accelerates membrane repolarization in a voltage-dependent manner and actively improves the time resolution of synaptic integration. We demonstrate that a somatically biased gradient of Kv1 channels underlies the degree of compensation for passive cable filtering during propagation of EPSPs in dendrites. Thus both the spatial distribution and properties of Kv1 channels play a key role in preserving binaural synaptic timing.

SUMMARY The cerebellum stores associative motor memories essential for properly timed movement; however, the mechanisms by which these memories form and are acted upon remain unclear. To determine how cerebellar activity relates to movement and motor learning, we used optogenetics to manipulate spontaneously firing Purkinje neurons (PNs) in mouse simplex lobe. Using high-speed videography and motion tracking, we found that altering PN activity produced rapid forelimb movement. PN inhibition drove movements time-locked to stimulus onset, whereas PN excitation drove delayed movements time-locked to stimulus offset. Pairing either PN inhibition or excitation with sensory stimuli triggered the formation of robust, associative motor memories; however, PN excitation led to learned movements whose timing more closely matched training intervals. These findings implicate inhibition of PNs as a teaching signal, consistent with a model whereby learning leads first to reductions in PN firing that subsequently instruct circuit changes in the cerebellar nucleus.

Climbing fiber (CF) input to the cerebellum is thought to instruct associative motor memory formation through its effects on multiple sites within the cerebellar circuit. We used adeno-associated viral delivery of channelrhodopsin-2 (ChR2) to inferior olivary neurons to selectively express ChR2 in CFs, achieving nearly complete transfection of CFs in the caudal cerebellar lobules of rats. As expected, optical stimulation of ChR2-expressing CFs generates complex spike responses in individual Purkinje neurons (PNs); in addition we found that such stimulation recruits a network of inhibitory interneurons in the molecular layer. This CF-driven disynaptic inhibition prolongs the postcomplex spike pause observed when spontaneously firing PNs receive direct CF input; such inhibition also elicits pauses in spontaneously firing PNs not receiving direct CF input. Baseline firing rates of PNs are strongly suppressed by low-frequency (2 Hz) stimulation of CFs, and this suppression is partly relieved by blocking synaptic inhibition. We conclude that CF-driven, disynaptic inhibition has a major influence on PN excitability and contributes to the widely observed negative correlation between complex and simple spike rates. Because they receive input from many CFs, molecular layer interneurons are well positioned to detect the spatiotemporal patterns of CF activity believed to encode error signals. Together, our findings suggest that such inhibition may bind together groups of Purkinje neurons to provide instructive signals to downstream sites in the cerebellar circuit.

Principal neurons of the medial superior olive (MSO) compute azimuthal sound location by integrating phase-locked inputs from each ear. While previous experimental and modeling studies have proposed that voltage-gated sodium channels (VGSCs) play an important role in synaptic integration in the MSO, these studies appear at odds with the unusually weak active backpropagation of action potentials into the soma and dendrites. To understand the spatial localization and biophysical properties of VGSCs, we isolated sodium currents in MSO principal neurons in gerbil brainstem slices. Nucleated and cell-attached patches revealed that VGSC density at the soma is comparable to that of many other neuron types, but channel expression is largely absent from the dendrites. Further, while somatic VGSCs activated with conventional voltage dependence (V 1/2 ϭ Ϫ30 mV), they exhibited an unusually negative range of steady-state inactivation (V 1/2 ϭ Ϫ77 mV), leaving ϳ92% of VGSCs inactivated at the resting potential (approximately Ϫ58 mV). In current-clamp experiments, non-inactivated VGSCs were sufficient to amplify subthreshold EPSPs near action potential threshold, counterbalancing the suppression of EPSP peaks by low voltage-activated potassium channels. EPSP amplification was restricted to the perisomatic region of the neuron, and relatively insensitive to preceding inhibition. Finally, computational modeling showed that the exclusion of VGSCs from the dendrites equalizes somatic EPSP amplification across synaptic locations and lowered the threshold for bilateral versus unilateral excitatory synaptic inputs. Together, these findings suggest that the pattern of sodium channel expression in MSO neurons contributes to these neurons' selectivity for coincident binaural inputs.