P1: KKK/mbg/vks/spd P2: KKK/PLB QC: PSADecember 31, 1998 9:34 Annual Reviews AR077-19Annu. Rev. Physiol. 1999. 61:477–96Copyrightc1999 by Annual Reviews. All rights reservedSYNAPTIC MECHANISMSFOR CODING TIMING INAUDITORY NEURONSLaurence O. TrussellDepartment of Physiology, University of Wisconsin, Madison, Wisconsin 53706;e-mail: [email protected] WORDS: glutamate receptors, potassium channels, synapses, plasticityABSTRACTNeurons in the cochlear ganglion and auditory brain stem nuclei preserve therelative timing of action potentials passed through sequential synaptic levels. Toaccomplish this task, these neurons have unique morphological and biophysicalspecializations in axons, dendrites, and nerve terminals. At the membrane level,these adaptations include low-threshold, voltage-gated potassium channels andunusually rapid-acting transmitter-gatedchannels, which govern howquicklyandreliably action potential threshold is reached during a synaptic response. Somenerve terminals are remarkably large and release large amounts of excitatoryneurotransmitter. The high output of transmitter at these terminals can lead tosynaptic depression, which may itself be regulated by presynaptic transmitterreceptors. The way in which these different cellular mechanisms are employedvariesindifferentcell types andcircuits and reflectsrefinements suited todifferentaspects of acoustic processing.THE TEMPORAL CODE IN AUDITIONIn order to convey information about pitch, intensity, and location, the audi-tory system takes advantage of place, rate, and temporal codes. An anatomicalmap of acoustic frequency is generated in the cochlea by the tonotopic re-sponse of the hair cell epithelium (1). While the spatial pattern of activationof this array and the firing rate of its auditory nerve output encode informa-tion, the timing of action potentials is the lingua franca of auditory processing,4770066-4278/99/0315-0477$08.00P1: KKK/mbg/vks/spd P2: KKK/PLB QC: PSADecember 31, 1998 9:34 Annual Reviews AR077-19478 TRUSSELLused by a wide variety of neurons to convey specific aspects of the acousticenvironment.The temporal code appears in different forms. Phase-locking occurs whenthe onset of an action potential appears reproducibly at a particular part of thecycle of the stimulating sound source (1a). While phase-locking is a typicalfeature of the response to low-frequency sound (<∼1–2 kHz), phase-lockedfiring of action potentials may also occur with respect to the cycle of amplitudemodulation of a high-frequency carrier (2). In some cases, neurons are adaptedto preserving the timing of action potentials with respect to action potentials inother circuits rather than to the sound cycle itself (3). For other neurons, theprecision of action potential timing may be retained just in the earliest part ofan acoustic response, such as when an onset must be encoded. Neural circuits,which use timing to extract the location and meaning of sounds, are discussedin this volume (3a).Several principles are played out in the cellular adaptions that permit theconveyance of timing. The surety and consistent timing of the response areessential to transmitting the onset and frequency of an acoustic stimulus and topromote entrainment. As signals are passaged from synapse to axon to synapse,conductionandsynapticdelays inevitablyaccumulate; the processing of tempo-ral information, particularly when convergence is an issue, requires that thesedelays be highly uniform, despite the inherently probabilistic nature of ionchannel gating and transmitter release. Uniform latencies are achieved in partby the large size of the excitatory synaptic potential (EPSP), which ensuresthat the variability or jitter in the timing of threshold crossing is kept short (4).The shape of the EPSP is fundamental to auditory timing circuits, since narrowEPSPs help minimize temporal summation and ensure a brief refractory period.In this review, we examine how the timing of action potentials can be preservedand transmitted through different synaptic levels in the auditory system, focus-ing on the mechanisms by which brief, well-timed EPSPs are generated andhow their amplitude may be regulated.SYNAPTIC MORPHOLOGY AND TIMINGIn bushy cells of the mammalian ventral cochlear nucleus (VCN) and in theiravian homologs of the nucleus magnocellularis (nMAG), as well as in principalcells of the mammalian medial nucleus of the trapezoid body (MNTB) and theventral nucleus of the lateral lemniscus, somatic innervation by large calycealor end-bulb terminals, which feature large numbers of functional synaptic re-leasesites per axonterminal, facilitates reliable transmission(5–8). In sphericalbushycells, MNTB, andnMAG, asingle stimulus liberates100–200transmitterquanta from each axon terminal, as indicated by quantal analysis (9–11). ThisP1: KKK/mbg/vks/spd P2: KKK/PLB QC: PSADecember 31, 1998 9:34 Annual Reviews AR077-19SYNAPTIC MECHANISMS IN AUDITION 479bolus of transmitter generates an excitatory postsynaptic current (EPSC) morethan 30 times larger than that needed to drive an action potential (4, 11). Theresulting EPSP reaches threshold quickly and reliably, despite considerableuse-dependent rundown (see below). Somatic innervation avoids the slowingof the onset that dendritic innervation would produce (12). However, despitethe apparent adaptive significance of somatic innervation, the octopus cells ofthe VCN (13), the neurons of the mammalian medial superior olive (MSO)(14), their avian homolog the nucleus laminaris (NL) (15,16), and to a lesserextent the lateral superior olive (LSO) (3) and the stellate cells of the VCN (17)combine dendrites and good timing, possibly because of biophysical special-izations that compensate for cable effects. Moreover, in these dendritic cellsand in the globular bushy cells of the VCN, convergence of many axonal inputsis favored over the presence of only a few massive synapses.CONTROL OF EPSC DURATIONSynaptic RecordingsThe duration of the EPSC is the starting point for controlling the time course ofEPSPs in neurons (reviewed in reference 18). EPSPs in auditory neurons mustbe brief in order to accommodate rapid transmission and minimize temporaldistortion through synaptic networks, and brief EPSPs can be achieved onlyby having short EPSCs. A short membrane time constant (RmCm), generallyinfluenced by resting potassium conductances, is also important (see below);however, a large synaptic conductance will itself lower the