Principles underlying sensory map topography in primary visual cortex.

The primary visual cortex contains a detailed map of the visual scene, which is represented according to multiple stimulus dimensions including spatial location, ocular dominance and stimulus orientation. The maps for spatial location and ocular dominance arise from the spatial arrangement of thalamic afferent axons in the cortex. However, the origins of the other maps remain unclear. Here we show that the cortical maps for orientation, direction and retinal disparity in the cat (Felis catus) are all strongly related to the organization of the map for spatial location of light (ON) and dark (OFF) stimuli, an organization that we show is OFF-dominated, OFF-centric and runs orthogonal to ocular dominance columns. Because this ON-OFF organization originates from the clustering of ON and OFF thalamic afferents in the visual cortex, we conclude that all main features of visual cortical topography, including orientation, direction and retinal disparity, follow a common organizing principle that arranges thalamic axons with similar retinotopy and ON-OFF polarity in neighbouring cortical regions.

Long-Term Depression Induced by Optogenetically Driven Nociceptive Inputs to Trigeminal Nucleus Caudalis or Headache Triggers.

The peripheral trigeminovascular pathway mediates orofacial and craniofacial pain and projects centrally to the brainstem trigeminal nucleus caudalis (TNc). Sensitization of this pathway is involved in many pain conditions, but little is known about synaptic plasticity at its first central synapse. We have taken advantage of optogenetics to investigate plasticity selectively evoked at synapses of nociceptive primary afferents onto TNc neurons. Based on immunolabeling in the trigeminal ganglia, TRPV1-lineage neurons comprise primarily peptidergic and nonpeptidergic nociceptors. Optical stimulation of channelrhodopsin-expressing axons in the TRPV1/ChR2 mouse in TNc slices thus allowed us to activate a nociceptor-enriched subset of primary afferents. We recorded from lamina I/II neurons in acutely prepared transverse TNc slices, and alternately stimulated two independent afferent pathways, one with light-activated nociceptive afferents and the other with electrically-activated inputs. Low-frequency optical stimulation induced robust long-term depression (LTD) of optically-evoked EPSCs, but not of electrically-evoked EPSCs in the same neurons. Blocking NMDA receptors or nitric oxide synthase strongly attenuated LTD, whereas a cannabinoid receptor 1 antagonist had no effect. The neuropeptide PACAP-38 or the nitric oxide donors nitroglycerin or sodium nitroprusside are pharmacologic triggers of human headache. Bath application of any of these three compounds also persistently depressed optically-evoked EPSCs. Together, our data show that LTD of nociceptive afferent synapses on trigeminal nucleus neurons is elicited when the afferents are activated at frequencies consistent with the development of central sensitization of the trigeminovascular pathway.SIGNIFICANCE STATEMENT Animal models suggest that sensitization of trigeminovascular afferents plays a major role in craniofacial pain syndromes including primary headaches and trigeminal neuralgia, yet little is known about synaptic transmission and plasticity in the brainstem trigeminal nucleus caudalis (TNc). Here we used optogenetics to selectively drive a nociceptor-enriched population of trigeminal afferents while recording from superficial laminae neurons in the TNc. Low-frequency optical stimulation evoked robust long-term depression at TRPV1/ChR2 synapses. Moreover, application of three different headache trigger drugs also depressed TRPV1/ChR2 synapses. Synaptic depression at these primary afferent synapses may represent a newly identified mechanism contributing to central sensitization during headache.

The effect of Wi-Fi electromagnetic waves on neuronal response properties in rat barrel cortex.

There is a growing number of studies on the possible biological effects of Wi-Fi radiations on nervous system. In this study we investigated the effect of Wi-Fi exposure on single neuron responses to natural stimuli by using whisker to barrel pathway. This study was done on 29 male Wistar rats. Neuronal spontaneous activity and ON and OFF responses to displacement of principal whisker (PW), adjacent whisker (AW) and combination of PW-AW stimulation (as natural stimuli) were recorded in barrel cortex of anaesthetised rats. A D-link Wi-Fi device was used for 1 h exposure to 2.4 GHz microwaves in data mode (18.2 dBm and 44% for power and duty cycle). A condition test ratio (CTR) was calculated for assessing neuronal integrative properties. Wi-Fi radiations decreased CTR for ON responses. However, neuronal spontaneous activity and ON and OFF responses were not significantly changed following exposure to Wi-Fi signals. The results of this study demonstrated that exposure to Wi-Fi radiation could modulate integrative responses to natural stimuli in barrel cortex.

The magnetite-based receptors in the beak of birds and their role in avian navigation.

Iron-rich structures have been described in the beak of homing pigeons, chickens and several species of migratory birds and interpreted as magnetoreceptors. Here, we will briefly review findings associated with these receptors that throw light on their nature, their function and their role in avian navigation. Electrophysiological recordings from the ophthalmic nerve, behavioral studies and a ZENK-study indicate that the trigeminal system, the nerves innervating the beak, mediate information on magnetic changes, with the electrophysiological study suggesting that these are changes in intensity. Behavioral studies support the involvement of magnetite and the trigeminal system in magnetoreception, but clearly show that the inclination compass normally used by birds represents a separate system. However, if this compass is disrupted by certain light conditions, migrating birds show 'fixed direction' responses to the magnetic field, which originate in the receptors in the beak. Together, these findings point out that there are magnetite-based magnetoreceptors located in the upper beak close to the skin. Their natural function appears to be recording magnetic intensity and thus providing one component of the multi-factorial 'navigational map' of birds.

Excitatory cortical neurons form fine-scale functional networks.

The specificity of cortical neuron connections creates columns of functionally similar neurons spanning from the pia to the white matter. Here we investigate whether there is an additional, finer level of specificity that creates subnetworks of excitatory neurons within functional columns. We tested for fine-scale specificity of connections to cortical layer 2/3 pyramidal neurons in rat visual cortex by using cross-correlation analyses of synaptic currents evoked by photostimulation. Recording simultaneously from adjacent layer 2/3 pyramidal cells, we find that when they are connected to each other (20% of all recorded pairs) they share common input from layer 4 and within layer 2/3. When adjacent layer 2/3 neurons are not connected to each other, they share very little (if any) common excitatory input from layers 4 and 2/3. In contrast, all layer 2/3 neurons share common excitatory input from layer 5 and inhibitory input from layers 2/3 and 4, regardless of whether they are connected to each other. Thus, excitatory connections from layer 4 to layer 2/3 and within layer 2/3 form fine-scale assemblies of selectively interconnected neurons; inhibitory connections and excitatory connections from layer 5 link neurons across these fine-scale subnetworks. Relatively independent subnetworks of excitatory neurons are therefore embedded within the larger-scale functional architecture; this allows neighbouring neurons to convey information more independently than suggested by previous descriptions of cortical circuitry.

Electromagnetic field and TGF-ß enhance the compensatory plasticity after sensory nerve injury in cockroach Periplaneta americana.

Recovery of function after sensory nerves injury involves compensatory plasticity, which can be observed in invertebrates. The aim of the study was the evaluation of compensatory plasticity in the cockroach (Periplaneta americana) nervous system after the sensory nerve injury and assessment of the effect of electromagnetic field exposure (EMF, 50 Hz, 7 mT) and TGF-ß on this process. The bioelectrical activities of nerves (pre-and post-synaptic parts of the sensory path) were recorded under wind stimulation of the cerci before and after right cercus ablation and in insects exposed to EMF and treated with TGF-ß. Ablation of the right cercus caused an increase of activity of the left presynaptic part of the sensory path. Exposure to EMF and TGF-ß induced an increase of activity in both parts of the sensory path. This suggests strengthening effects of EMF and TGF-ß on the insect ability to recognize stimuli after one cercus ablation. Data from locomotor tests proved electrophysiological results. The takeover of the function of one cercus by the second one proves the existence of compensatory plasticity in the cockroach escape system, which makes it a good model for studying compensatory plasticity. We recommend further research on EMF as a useful factor in neurorehabilitation.

Thrombin induces long-term potentiation of reactivity to afferent stimulation and facilitates epileptic seizures in rat hippocampal slices: toward understanding the functional consequences of cerebrovascular insults.

The effects of thrombin, a blood coagulation serine protease, were studied in rat hippocampal slices, in an attempt to comprehend its devastating effects when released into the brain after stroke and head trauma. Thrombin acting through its receptor, protease-activated receptor 1 (PAR1), produced a long-lasting enhancement of the reactivity of CA1 neurons to afferent stimulation, an effect that saturated the ability of the tissue to undergo tetanus-induced long-term potentiation. This effect was mediated by activation of a PAR1 receptor, because it was shared by a PAR1 agonist, and was blocked by its selective antagonist. An independent effect of thrombin involved the lowering of the threshold for generating epileptic seizures in CA3 region of the hippocampus. Thus, the experiments in a slice mimicked epileptic and cognitive dysfunction induced by thrombin in the brain, and suggest that these effects are mediated by activation of the PAR1 receptor.

Electroreceptor neuron dynamics shape information transmission.

The gymnotiform weakly electric fish Apteronotus leptorhynchus can capture prey using electrosensory cues that are dominated by low temporal frequencies. However, conventional tuning curves predict poor electroreceptor afferent responses to low-frequency stimuli. We compared conventional tuning curves with information tuning curves and found that the latter predicted substantially improved responses to these behaviorally relevant stimuli. Analysis of receptor afferent baseline activity showed that negative correlations reduced low-frequency noise levels, thereby increasing information transmission. Multiunit recordings from receptor afferents showed that this increased information transmission could persist at the population level. Finally, we verified that this increased low-frequency information is preserved in the spike trains of central neurons that receive receptor afferent input. Our results demonstrate that conventional tuning curves can be misleading when certain noise reduction strategies are used by the nervous system.

Pain perception and laser evoked potentials during menstrual cycle in migraine.

The association between estrogens "withdrawal" and attacks of migraine without aura is well-known. The aim of the study was to examine the features of laser evoked potentials (LEPs), including habituation, in women suffering from migraine without aura versus healthy controls, during the pre-menstrual and late luteal phases. Nine migraine without aura and 10 non-migraine healthy women, were evaluated during the pre-menstrual phase and late luteal phase. The LEPs were recorded during the inter-critical phase. The right supraorbital zone and the dorsum of the right hand were stimulated. Three consecutive series of 20 laser stimuli were obtained for each stimulation site. Laser pain perception was rated by a 0-100 VAS after each stimulation series. Migraine patients exhibited increased LEPs amplitude and reduced habituation compared to normal subjects. Laser-pain perception was increased during the pre-menstrual phase in both patients and controls. Migraine patients and controls showed increased P2 and N2-P2 amplitude in the pre-menstrual phase, on both stimulation sites. During the pre-menstrual phase the N2-P2 habituation appeared to be reduced in both migraine and healthy women. The estrogen withdrawal occurring during the menstrual cycle may favor reduced habituation of nociceptive cortex, which may facilitate pain symptoms and migraine in predisposed women.

Frequency control of motor patterning by negative sensory feedback.

The sensory system plays a key role in the generation of behavior by providing the nervous system with information about the environment and feedback about body movements such that motor output can continuously be adapted to changing circumstances. Although the effects of sensory organs on nervous system function have been demonstrated in many systems, the impact of sensory activity has rarely been studied in conditions in which motor output and sensory activity can interact as they do in behaving animals. In such situations, emergent properties may surface and govern the characteristics of the motor system. We studied the dynamics of sensorimotor interaction with a combination of electrophysiological experiments and computational modeling in the locust flight pattern generator, including its sensory components. The locust flight motor output is produced by a central pattern generator that interacts with phasic sensory feedback from the tegula, a proprioceptor that signals downstroke movement of the wing. We modeled the flight control system, and we tested the model predictions by replacing tegula feedback in the animal with artificial feedback through computer-controlled electric stimulation of the appropriate sensory nerves. With reference to the cycle frequency in the locust flight rhythm, our results show that motor patterns can be regulated via the variation of sensory feedback loops. In closed-loop conditions, tegula feedback strength determines cycle frequency in the model and the biological preparation such that stronger feedback results in lower frequencies. This regulatory mechanism appears to be a general emergent property of negative feedback systems.

High-frequency afferent stimulation induces long-term potentiation of field potentials in the ventral tegmental area.

Excitatory synapses on dopamine neurons in the VTA can undergo both long-term potentiation and depression. Additionally, drug-induced plasticity has been found at VTA synapses, and is proposed to play a role in reward-related learning and addiction by modifying dopamine cell firing. LTP at these synapses is difficult to generate experimentally in that it requires an undisturbed intracellular milieu and is often small in magnitude. Here, we demonstrate the induction of LTP as a property of evoked field potentials within the VTA. Excitatory field potentials were recorded extracellularly from VTA neurons in acute horizontal midbrain slices. Using extracellular and intracellular recording techniques, we found that evoked field potentials originate within the VTA itself and are largely composed of AMPA receptor-mediated EPSPs and action potentials triggered by activation of glutamatergic synapses on both dopamine and GABA neurons. High-frequency afferent stimulation (HFS) induced LTP of the field potential. The induction of this LTP was blocked by application of the NMDAR antagonist, d-APV, prior to HFS. As reported previously, glutamatergic synapses on GABA neurons did not express LTP while those on dopamine neurons did. We conclude that the potentiation of glutamatergic synapses on dopamine neurons is a major contributor to NMDA receptor-dependent LTP of the field potential. Field potential recordings may provide a convenient approach to explore the basic electrophysiological properties of VTA neurons and the development of addiction-related processes in this brain region.

Influences of entopeduncular nucleus stimulation upon electromyogram activity of masticatory muscles.

Influences of stimulation of the entopeduncular nucleus (Ep) upon electromyogram (EMG) activity of masticatory muscles were examined. In the rat lightly anesthetized with halothane, high frequency (HF) microstimulation (trains of 20, 333-Hz cathodal pulses at 30-60 microA) and GABA microinjection (0.2-0.6 microl of 10 mM GABA dissolved in physiological saline) were performed in the Ep by using a three-barreled microelectrode. EMG activity was recorded from the anterior digastrics and the anterior superficial masseter muscles by using two fine enamel-insulated copper wires. The EMG activity was also evoked by the GABA microinjection. The effect of the GABA microinjection was negated by the microinjection of bicuculline prior to the GABA microinjection. The EMG activity was classified into the tonic spike-type, burst-type, or mixed type on the basis of the waveform. In each rat, the location of the microelectrode tip was estimated by observing a series of serial frontal sections through the whole rostrocaudal extent of the Ep. The present data suggested that Ep neurons involved in elicitation of tonic spike-type activity in the jaw muscles might be located mainly in the rostral third of the Ep, and that Ep neurons implicated in provocation of burst-type activity in jaw muscles might be located in the caudal third of the Ep. Possible neuronal pathways from the Ep to motoneurons innervating the masticatory muscles were discussed. The present data shed new light on the control mechanisms of the basal ganglia upon jaw movements.

Somatostatin inhibits activation of dorsal cutaneous primary afferents induced by antidromic stimulation of primary afferents from an adjacent thoracic segment in the rat.

To investigate the effect of somatostatin on the cross-excitation between adjacent primary afferent terminals in the rats, we recorded single unit activity from distal cut ends of dorsal cutaneous branches of the T10 and T12 spinal nerves in response to antidromic stimulation of the distal cut end of the T11 dorsal root in the presence and absence of somatostatin and its receptor antagonist applied to the receptive field of the recorded nerve. Afferent fibers were classified based upon their conduction velocity. Mean mechanical thresholds decreased and spontaneous discharge rates increased significantly in C and Adelta but not Abeta fibers of the T10 and T12 spinal nerves in both male and female rats following antidromic electrical stimulation (ADES) of the dorsal root from adjacent spinal segment (DRASS) indicating cross-excitation of thin fiber afferents. The cross-excitation was not significantly different between male and female rats. Microinjection of somatostatin into the receptive field of recorded units inhibited the cross-excitation. This inhibitory effect, in turn, was reversed by the somatostation receptor antagonist cyclo-somatostatin (c-SOM). Application of c-SOM alone followed by ADES of DRASS significantly decreased the mechanical thresholds and increased the discharge rates of C and Adelta fibers, indicating that endogenous release of somatostatin plays a tonic inhibitory role on the cross-excitation between peripheral nerves. These results suggest that somatostatin could inhibit the cross-excitation involved in peripheral hyperalgesia and have a peripheral analgesic effect.

Peripheral repetitive magnetic stimulation induces intracortical inhibition in healthy subjects.

OBJECTIVE: Repetitive magnetic stimulation (rMS) is mainly used in transcranial applications. Only a few works have described its potential peripheral use. The aim of this investigation was to determine if conditioning peripheral (paravertebral) rMS of the cervical nerve roots in a group of healthy subjects induces changes in motor cortical excitability. METHODS: This was measured by means of motor evoked potentials (MEP), motor recruitment curves (RC), intracortical inhibition (ICI) and facilitation, as well as the cortical silent period (CSP) before and after repetitive stimulation. rMS was carried out by applying ten series of stimulation at 120% of resting motor threshold, each lasting 10 seconds with a frequency of 20 Hz. The nerve roots (C7/C8) of the right hand innervating the target muscles (the first dorsal interosseous) were systematically stimulated. RESULTS: This conditioning rMS caused a significantly longer CSP (p=0.001), increased MEP amplitudes (with a tendency to significance of p=0.06) and raised ICI (p<0.05). These changes were absent on the contralateral side, as well as in the course of RC. In conclusion, previously published results that described a prolonged CSP and increased MEP amplitudes led us to speculate that conditioning peripheral rMS is, like electrical stimulation, capable of influencing motor cortical excitability. SIGNIFICANCE: rMS might therefore be used in rehabilitative strategies for spasticity, pain or central paresis.

Abnormal neuronal response to rectal and anal stimuli in patients treated with primary radiotherapy for anal cancer.

INTRODUCTION: Sphincter-sparing radiotherapy or chemoradiation (RT/CRT) have become the standard treatments for most patients with anal cancer. Unfortunately, long-term survivors often suffer from severe bowel symptoms indicating sensory dysfunction. The aim of the present study was to characterize the sensory pathways of the brain-gut axis after radiotherapy for anal cancer. METHOD: Cortical evoked potentials (CEPs) were recorded during repeated, rapid balloon distensions of the rectum and anal canal in 13 patients with anal cancer treated with radiotherapy or chemoradiation and in 17 healthy volunteers. Latencies and amplitudes of rectal CEPs were compared between the groups. CEPs from both rectal and anal distensions were examined using single sweep spectral band analysis to determine the relative amplitude of five spectral bands as a proxy of neuronal processing. RESULTS: Groups were comparable by age (62.4 ±â€¯7.8 vs 58.9 ±â€¯8.9, p < 0.32) and gender. Patients had a mean Wexner fecal incontinence score of 5.5 (±3.8) and median LARS Score of 29 (0-39). Rectal CEP latencies were prolonged in patients (F = 11.7; p < 0.001), whereas amplitudes were similar (F = 0.003; p = 0.96). Spectral analysis of CEPs from rectal distensions showed significant differences between groups in theta (4-8 Hz), alpha (8-12 Hz), beta (12-32 Hz) and gamma (32-70 Hz) bands (all p < 0.001) and CEPs from anal distensions showed significant differences in the alpha, beta and gamma bands (all p ≤ 0.002). CONCLUSION: Patients treated with RT/CRT for anal cancer have impaired ano-rectal sensory pathways and abnormal cortical processing. This may play a central role for the pathogenesis of late proctopathy.

G-protein-coupled GABAB receptors inhibit Ca2+ channels and modulate transmitter release in descending turtle spinal cord terminal synapsing motoneurons.

Presynaptic gamma-aminobutyric acid type B receptors (GABA(B)Rs) regulate transmitter release at many central synapses by inhibiting Ca(2+) channels. However, the mechanisms by which GABA(B)Rs modulate neurotransmission at descending terminals synapsing on motoneurons in the spinal cord remain unexplored. To address this issue, we characterized the effects of baclofen, an agonist of GABA(B)Rs, on the monosynaptic excitatory postsynaptic potentials (EPSPs) evoked in motoneurons by stimulation of the dorsolateral funiculus (DLF) terminals in a slice preparation from the turtle spinal cord. We found that baclofen depressed neurotransmission in a dose-dependent manner (IC(50) of approximately 2 microM). The membrane time constant of the motoneurons did not change, whereas the amplitude ratio of the evoked EPSPs in response to a paired pulse was altered in the presence of the drug, suggesting a presynaptic mechanism. Likewise, the use of N- and P/Q-type Ca(2+) channel antagonists (omega-conotoxin GVIA and omega-agatoxin IVA, respectively) also depressed EPSPs significantly. Therefore, these channels are likely involved in the Ca(2+) influx that triggers transmitter release from DLF terminals. To determine whether the N and P/Q channels were regulated by GABA(B)R activation, we analyzed the action of the toxins in the presence of baclofen. Interestingly, baclofen occluded omega-conotoxin GVIA action by approximately 50% without affecting omega-agatoxin IVA inhibition, indicating that the N-type channels are the target of GABA(B)Rs. Lastly, the mechanism underlying this effect was further assessed by inhibiting G-proteins with N-ethylmaleimide (NEM). Our data show that EPSP depression caused by baclofen was prevented by NEM, suggesting that GABA(B)Rs inhibit N-type channels via G-protein activation.

Inactivation of prefrontal cortex abolishes cortical acetylcholine release evoked by sensory or sensory pathway stimulation in the rat.

Sensory stimulation and electrical stimulation of sensory pathways evoke an increase in acetylcholine release from the corresponding cortical areas. The pathways by which such sensory information reaches the cholinergic neurons of the basal forebrain that are responsible for this release are unclear, but have been hypothesized to pass through the prefrontal cortex (PFC). This hypothesis was tested in urethane-anesthetized rats using microdialysis to collect acetylcholine from somatosensory, visual, or auditory cortex, before and after the PFC was inactivated by local microdialysis delivery of the GABA-A receptor agonist muscimol (0.2% for 10 min at 2 microl/min). Before PFC inactivation, peripheral sensory stimulation and ventral posterolateral thalamic stimulation evoked 60 and 105% increases, respectively, in acetylcholine release from somatosensory cortex. Stimulation of the lateral geniculate nucleus evoked a 57% increase in acetylcholine release from visual cortex and stimulation of the medial geniculate nucleus evoked a 72% increase from auditory cortex. Muscimol delivery to the PFC completely abolished each of these evoked increases (overall mean change from baseline = -7%). In addition, the spontaneous level of acetylcholine release in somatosensory, visual, and auditory cortices was reduced by 15-59% following PFC inactivation, suggesting that PFC activity has a tonic facilitatory influence on the basal forebrain cholinergic neurons. These experiments demonstrate that the PFC is necessary for sensory pathway evoked cortical ACh release and strongly support the proposed sensory cortex-to-PFC-to-basal forebrain circuit for each of these modalities.

Absence of linear correlation between fluctuations in area of simultaneous recorded monosynaptic responses and Hoffmann's reflexes in the rat.

In this study we analyze the possible relationship between fluctuations in area of monosynaptic reflex responses (MSR) and Hoffmann's reflex (H reflexes) in the plantar closed loop pathway of the anesthetized rat. These reflexes were evoked by low-frequency stimuli applied to the sciatic nerve or lateral plantar nerve and then concurrently recorded on the distal tibial nerve or lateral plantar nerve, respectively as well as the lateral plantar muscles in the foot of the anesthetized rat. From trial to trial, H reflexes showed higher variability in area than MSR, whether the latter was recorded in the distal tibial nerve (n=8 experiments) or in the lateral plantar nerve (n=5 experiments). No linear correlation was found between changes in area of concurrently evoked MSR and H reflexes (r(MSR-H,n=8)=0.11+/-0.03 and r(MSR-H,n=5)=0.08+/-0.09, respectively). These findings suggest that trial-to-trial fluctuations in area of H reflexes may involve interaction of several sources of variation, among others to MSR variability (due to pre-, and post-synaptic factors influencing the excitability of spinal motoneurons) in combination with those related to peripheral mechanisms, such as trial to trial activation of a different number of muscle fibers, either by the probabilistic transmitter release from neuromuscular junctions, by activation of motor units of variable size or to fluctuations in excitability of muscle fibers.

[Change of afferent impulsing of peripheral nerve caused by polarized light with various wave lengths].

Change of impulse activity in branches of n. saphenus caused by influence of linearly polarized light with various wave lengths on the skin of rat's hind limb was studied. It was established that polarized light effect on skin receptor endings depended on wave length. Exposure of skin to red and blue parts of spectrum increased afferent impulsing of peripheral nerve for a short time, and influence of polychromatic polarized light (400-2000 nm) significantly decreased it for a long time (like lidocaine effect).

Presynaptic Na+ channels: locus, development, and recovery from inactivation at a high-fidelity synapse.

Na+ channel recovery from inactivation limits the maximal rate of neuronal firing. However, the properties of presynaptic Na+ channels are not well established because of the small size of most CNS boutons. Here we study the Na+ currents of the rat calyx of Held terminal and compare them with those of postsynaptic cells. We find that presynaptic Na+ currents recover from inactivation with a fast, single-exponential time constant (24 degrees C, tau of 1.4-1.8 ms; 35 degrees C, tau of 0.5 ms), and their inactivation rate accelerates twofold during development, which may contribute to the shortening of the action potential as the terminal matures. In contrast, recordings from postsynaptic cells in brainstem slices, and acutely dissociated, reveal that their Na+ currents recover from inactivation with a double-exponential time course (tau(fast) of 1.2-1.6 ms; tau(slow) of 80-125 ms; 24 degrees C). Surprisingly, confocal immunofluorescence revealed that Na+ channels are mostly absent from the calyx terminal but are instead highly concentrated in an unusually long (approximately 20-40 microm) unmyelinated axonal heminode. Outside-out patch recordings confirmed this segregation. Expression of Na(v)1.6 alpha-subunit increased during development, whereas the Na(v)1.2alpha-subunit was not present. Serial EM reconstructions also revealed a long pre-calyx heminode, and biophysical modeling showed that exclusion of Na+ channels from the calyx terminal produces an action potential waveform with a shorter half-width. We propose that the high density and polarized locus of Na+ channels on a long heminode are critical design features that allow the mature calyx of Held terminal to fire reliably at frequencies near 1 kHz.