Bursts of neuronal activity are transmitted more effectively as synapses mature. However, the mechanisms that control synaptic efficiency during development are poorly understood. Here, we study postnatal changes in synaptic ultrastructure and exocytosis in a calyx-type nerve terminal. Vesicle pool size, exocytotic efficiency (amount of exocytosis per Ca influx), Ca current facilitation, and the number of active zones (AZs) increased with age, whereas AZ area, number of docked vesicles per AZ, and release probability decreased with age. These changes led to AZs that are less prone to multivesicular release, resulting in reduced AMPA receptor saturation and desensitization. A greater multiplicity of small AZs with few docked vesicles, a larger pool of releasable vesicles, and a higher efficiency of release thus promote prolonged high-frequency firing in mature synapses.

The calyx of Held exhibits fast glutamatergic neurotransmission at high rates with low temporal jitter and has adapted specialized synaptic mechanisms to support its functional demands. We report the presence in calyces of an atypical arrangement of subcellular organelles, called the mitochondria-associated adherens complex (MAC). We demonstrate that MACs are located adjacent to synapses and contain membranous elements linked with coated and uncoated vesicles. Mitochondria that form MACs have more complex geometries than other mitochondria within the calyx and can extend between clusters of synapses. We estimate that the calyx contains 1600 MACs, 2400 synapses, and 6200 readily releasable vesicles. We also identify synaptic vesicle endocytotic regions close to MACs and synapses and hypothesize that calyces are composed of multiple activity modules, each containing machinery for vesicle release and recycling. The calyx of Held is one of the largest nerve terminals in the CNS (Held, 1893). Along with large and modified end-bulbs of Held delivered by auditory nerve fibers onto cochlear nucleus neurons (Cant and Morest, 1979;Tolbert and Morest, 1982;Fekete et al., 1984), these complex nerve terminals are key elements in brainstem circuitry that subserves sound localization (Morest, 1968). Spontaneous activity (generated in the absence of sound) can exceed 100 spikes/sec at the calyx terminal, and sound-driven activity at the most sensitive frequency of the calyceal neuron can approach 600 spikes/sec (Spirou et al., 1990). Temporal synchrony of calyceal neurons to a preferred phase of a low-frequency sound exceeds that found in the auditory nerve, and it can entrain (fire on every cycle of the stimulus sinusoid) at rates approaching 1 kHz (Joris et al., 1994a,b).High activity rates place demands on endocytotic mechanisms to maintain a pool of releasable vesicles. Some neurons, such as retinal bipolar cells, possess specialized structures called synaptic ribbons that are involved in vesicle trafficking, and therefore have unique mechanisms to solve their demands for synaptic activity (von Gersdorff and Matthews, 1999). It is plausible that the calyceal terminal, because of its extremely high spike rate and the temporal precision required to accomplish its task of sound localization, also uses unique structures and mechanisms.A noteworthy arrangement of organelles, consisting of a mitochondrion located near the presynaptic membrane and tethered via filaments to a punctum adherens, was first described in nerve terminals of the spinal cord (Gray, 1963). In the auditory system, this structure was noted in large and modified end-bulbs of auditory nerve fibers (Cant and Morest, 1979;Tolbert and Morest, 1982). More recently, we described this structure, which we named the mitochondria-associated adherens complex (MAC), in large collateral terminals of calyceal axons that are found in the superior olivary complex . Given the diversity of cellular elements that comprise the MAC, it could perform various functions in the nerve...

Persistent Post-Mastectomy Pain (PPMP) is a common condition that can follow surgeries for breast cancer, the most common cancer in women. Because of the frequency of PPMP and its potential severity, it has received increasing research attention. This manuscript reviews the recent research literature, beginning with a brief history and then relevant medical, surgical, demographic, and psychosocial risk factors. Subsequently, social, psychological, and functional sequelae that have been linked to PPMPS are considered, as is research on current pharmacological, psychological, and rehabilitative approaches to treatment. The review concludes with a discussion of directions for future research and treatment that might reduce the incidence and impact of PPMP on breast cancer survivors. PERSPECTIVE: This article describes current research literature involving mechanisms, risks, and treatments related to persistent post-mastectomy pain. Implications of research findings also are discussed for pre- and post-surgical approaches to pain management, current treatments, and promising research directions.

The sensitivity of medial superior olive (MSO) neurons to tens of microsecond differences in interaural temporal delay (ITD) derives in part from their membrane electrical characteristics, kinetics and timing of excitatory and inhibitory inputs, and dendrite structure. However, maturation of these physiological and structural characteristics are little studied, especially in relationship to the onset of auditory experience. We showed, using brain slices at physiological temperature, that MSO neurons exhibited sensitivity to simulated temporally delayed (TD) EPSCs (simEPSC), injected through the recording electrode, by the initial phase of hearing onset at P10, and TD sensitivity was reduced by block of low threshold potassium channels. The spike generation mechanism matured between P10 and P16 to support TD sensitivity to adult-like excitatory stimuli (1-4 ms duration) by P14. IPSP duration was shorter at physiological temperature than reported for lower temperatures, was longer than EPSP duration at young ages, but approached the duration of EPSPs by P16, when hearing thresholds neared maturity. Dendrite branching became less complex over a more restricted time frame between P10 and P12. Because many physiological and structural properties approximated mature values between P14 and P16, we studied temporal integration of simEPSCs and IPSPs at P15. Only a narrow range of relative onset times (< 1 ms) yielded responses showing sensitivity to TD. We propose that shaping of excitatory circuitry to mediate TD sensitivity can begin before airborne sound is detectable, and that inhibitory inputs having suboptimal neural delays may then be pruned by cellular mechanisms activated by sensitivity to ITD.