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I'm reading Kandel. Chapter 3 states the following:
Because the initial segment of the axon has the highest density of voltage-sensitive Na+ channels and therefore the lowest threshold for generating an action potential, an input signal spreading passively along the cell membrane is more likely to give rise to an action potential at the initial segment than at other sites in the cell.
I know it is possible to have dendritic spikes, which is an action potential given a much stronger input to open enough Na+ channels. But can there be a different action potential, not axonic nor dendritc, given that enough Na+ channels locally open in the cell membrane?
I've seen some papers talk about "somatic action potential", but its meaning and how it works I don't understand.
Regulation of Backpropagating Action Potentials in Mitral Cell Lateral Dendrites by A-Type Potassium Currents
Dendrodendritic synapses, distributed along mitral cell lateral dendrites, provide powerful and extensive inhibition in the olfactory bulb. Activation of inhibition depends on effective penetration of action potentials into dendrites. Although action potentials backpropagate with remarkable fidelity in apical dendrites, this issue is controversial for lateral dendrites. We used paired somatic and dendritic recordings to measure action potentials in proximal dendritic segments (0–200 μm from soma) and action potential-generated calcium transients to monitor activity in distal dendritic segments (200–600 μm from soma). Somatically elicited action potentials were attenuated in proximal lateral dendrites. The attenuation was not due to impaired access resistance in dendrites or to basal synaptic activity. However, a single somatically elicited action potential was sufficient to evoke a calcium transient throughout the lateral dendrite, suggesting that action potentials reach distal dendritic compartments. Block of A-type potassium channels (IA) with 4-aminopyridine (10 mM) prevented action potential attenuation in direct recordings and significantly increased dendritic calcium transients, particularly in distal dendritic compartments. Our results suggest that IA may regulate inhibition in the olfactory bulb by controlling action potential amplitudes in lateral dendrites.
The most common site for neurotransmitter release between neurons is at synaptic terminals located along or at the ends of axons. However, there are a significant number of brain regions where transmitter release occurs from dendrites or dendritic appendages (for review, see Kennedy and Ehlers, 2011). Although axonal transmitter release has been extensively studied in the mammalian brain, dendritic transmitter release has been difficult to study, owing in part to the difficulty in obtaining electrical recordings from fine dendritic structures. The thalamus is one area were dendrodendritic synaptic transmission is prevalent and experimentally approachable.
In mammals, visual information is passed from the retina to the visual cortex mainly through the dorsal lateral geniculate nucleus of the thalamus (LGNd). In the LGNd, retinal ganglion cells form excitatory synapses onto thalamocortical cells, which in turn project to layer 4 of the visual cortex. Interestingly, only 5–10% of terminals onto thalamocortical cells are from the retina, the primary sensory input to this region (Erişir et al., 1997b). The remainder of contacts onto thalamocortical cells arises from brainstem, layer 6 of visual cortex, reticular thalamus, and intrathalamic inhibitory neurons. These nonretinal synapses are believed to play a role in shaping the response of thalamocortical cells to retinal input. Of particular importance are inhibitory (GABA) connections, formed by local circuit neurons onto proximal regions of thalamocortical dendrites. Inhibitory interneurons have been implicated in controlling the precise spike timing of thalamocortical cells to retinal excitation, and in refinement of thalamocortical receptive fields (Sillito and Kemp, 1983 Berardi and Morrone, 1984 Guillery and Sherman, 2002 Blitz and Regehr, 2005). Canonically, this inhibition would be accomplished by generation of an action potential in response to retinal input, which would propagate along the interneuron axon causing vesicular GABAergic release from axonal terminals onto thalamocortical dendrites. Thalamic interneurons, however, are unique in that they express GABAergic vesicles not only in axonal boutons, but also in dendritic appendages (Famiglietti, 1970 Famiglietti and Peters, 1972 Rafols and Valverde, 1973 Montero, 1986). A majority of interneuron synapses in the LGNd are made by these dendritic boutons. While axonal release is typically controlled by action potential propagation into terminal boutons, it is less certain whether action potentials can propagate completely throughout the interneuron dendritic arbor to promote vesicle release from dendritic appendages. Although calcium imaging experiments have suggested that Na/K action potentials can propagate into the dendrites to promote calcium transients (Acuna-Goycolea et al., 2008), a direct measure of Na/K action potentials in the interneuron dendrite has been precluded by the dendrite's fine caliber.
In our study, we used a combination of high temporal and spatial resolution voltage-sensitive dye (VSD) imaging to demonstrate that trains of action potentials actively propagate throughout the entire interneuron dendrite and into dendritic appendages. Activation of tetrodotoxin (TTX)-sensitive Na + channels was necessary for dendritic action potential propagation, while tetraethylammonium chloride (TEA)-sensitive K + channels were important for dendritic action potential repolarization. Despite the active and reliable backpropagation of action potentials throughout the dendritic arbor, local synaptic inputs alone failed to initiate spikes in interneuron dendrites. Thus, the generation of an action potential in thalamic interneurons can result in a rapid and global inhibitory signal through the release of GABA from both axons as well as dendritic terminals.
Detailed three-dimensional reconstructions of 42 neurons were used. Two rat Purkinje cells, two rat neocortical layer 5 pyramidal neurons, and four rat substantia nigra dopamine neurons were filled with biocytin and digitally reconstructed using a ×100 oil immersion objective (1.4 NA) on a Zeiss Axioplan (Zeiss, Oberkochen, Germany) in conjunction with Neurolucida software (MicroBrightField, Colchester, VT). Three rat layer 5 pyramidal neurons were from G. Stuart and N. Spruston, and one from D. Smetters three guinea pig Purkinje cells were from M. Rapp rat CA1/CA3 pyramidal cells, and DG interneurons and granule cells were obtained from the Duke-Southampton Neuronal Morphology Archive (www.neuro.soton.ac.uk). Reconstructions were inspected carefully, and only those without apparent errors in connectivity or dendritic diameters were used. All dendrites were divided into compartments with a maximum length of 7 μm. Spines were incorporated where appropriate by scaling membrane capacitance and conductances (Holmes 1989 Shelton 1985).
Axonal initiation and active dendritic propagation of action potentials in substantia nigra neurons
The site of action potential initiation in substantia nigra neurons was investigated by using simultaneous somatic and dendritic whole-cell recording in brain slices. In many dopamine neurons, action potentials were observed first at the dendritic recording site. Anatomical reconstruction showed that in these neurons, the axon emerged from the dendrite from which the recording had been made. Action potentials showed little attenuation in the dendritic tree, which in dopamine neurons was shown to be due to recruitment of dendritic sodium channels and may be related to the dendritic release of dopamine. We conclude that in substantia nigra neurons, the site of action potential initiation, and thus the final site of synaptic integration, is in the axon. As the axon can originate from a dendrite, up to 240 μm away from the soma, synaptic input to the axon-bearing dendrite may be privileged with respect to its ability to influence action potential initiation.
Present address: Laboratoire de Neurobiologie, Ecole Normale Supe´rieure, 46 rue d'Ulm, 75005 Paris, France.
Present address: Laboratoire de Biologie Cellulaire de la Synapse, Ecole Normale Supe´rieure, 46 rue d'Ulm, 75005 Paris, France.
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We performed patch-clamp recordings from interneurons positive for enhanced green fluorescent protein (EGFP) near the border of stratum radiatum (SR) and stratum lacunosum-moleculare (SLM) of hippocampal area CA1 in acute slices prepared from serotonin 5b receptor (Htr5b) BAC transgenic mice (GENSAT 10 see Methods). Post-hoc staining of biocytin-filled interneurons revealed that these EGFP-positive interneurons had dendrites contained within the CA1 region. The axonal arborization was larger than the dendritic tree and occasionally extended into the neighboring CA3 region or subiculum, or crossed the hippocampal fissure to enter the dentate gyrus ( Fig. 1a ). Based on their location and dendritic and axonal arborizations, these are most likely perforant path-associated inhibitory interneurons 11 . The basic properties of these neurons are reported in Supplementary Table 1.
Persistent firing in Htr5b interneurons. (a) A biocytin-filled Htr5b-EGFP-positive interneuron near the SR-SLM border of hippocampal area CA1 (dendrites blue, axon red). A schematic representation of a CA1 pyramidal cell is also shown (DG = dentate gyrus). (b) Whole-cell current-clamp recording of persistent firing. To evoke persistent firing, a 1-second current step of 500 pA was delivered during each 10-second sweep (first 4 sweeps on the left sweeps 5 on the top right). In this example, the total number of evoked action potentials prior to persistent firing was 1151. (c) Persistent firing was also induced with 1-second current steps starting at 40 pA and incrementing the amplitude by 20 pA with each subsequent step (shown here is the response to the 11 th step, 240 pA, which induced persistent firing after a total of 296 action potentials). In this example, persistent firing lasted over one minute. The instantaneous firing frequency of each action potential is plotted below the recording. (d) Three representative cells showing the frequency of persistent firing over time after its onset. (e) Persistent firing duration measured from its onset to the last spike (n = 274). The red bar shows the cells where persistent firing outlasted the 4-minute recording period (n = 5). (f) Persistent firing in a layer 2/3 neocortical interneuron (somatosensory cortex) induced with the same protocol used in (c) only the final trace is shown. All data are from Htr5b-EGFP-positive hippocampal interneurons near the SR-SLM border.
Persistent firing in hippocampal interneurons
80% of the EGFP-positive interneurons (n = 214/274), repeated somatic current injections eventually triggered persistent firing that outlasted the current injection by seconds or minutes ( Fig. 1b𠄼 , Supplementary Fig. 1). Once initiated, the persistent firing frequency increased to a maximum firing rate of 52.1 ± 1.9 Hz occurring at 3.5 ± 0.2 sec after the end of the final stimulus ( Fig. 1d Supplementary Fig. 2, n = 187). In most neurons, persistent firing lasted for tens of seconds the median duration was 58 sec (n = 180) and 7 outlier cells had durations of 4 minutes ( Fig. 1e ).
Persistent firing was not an artifact of BAC transgenic EGFP expression, because it was also observed in 24% (n = 13/54) of EGFP-negative hippocampal interneurons in the Htr5b mice, only 8% (n = 1/13) of EGFP-positive hippocampal interneurons in Drd2 BAC transgenic mice, and 23% (n = 6/26) of hippocampal interneurons in wild-type C57BL/6 mice (Supplementary Fig. 3). Persistent firing was also observed in 17% of CA1 interneurons in rat hippocampal slices (n = 3/18), demonstrating that it occurs across species (Supplementary Fig. 3). These findings suggest that the persistent-firing interneurons are selectively labeled in Htr5b BAC transgenic mice. Given that persistent firing can be induced in interneurons of wild-type mice and rats, it is surprising that it has not been reported before. One possibility is that it has been observed, but never reported because it does not occur in all cells, thus making it hard to study systematically. Another possibility is that it has not been observed because slice physiologists typically do not stimulate cells with hundreds of action potentials (e.g., Supplementary Fig. 1c). Finally, persistent firing may have been missed because it is temperature sensitive it was only observed near physiological temperatures and never at room temperature (see Methods).
Persistent firing could also be induced in EGFP-positive interneurons of somatosensory cortex ( Fig. 1f ), although with a lower probability than in the hippocampus (n = 7/19 cells, 37% vs 78% in hippocampus, P < 0.0001). In addition, more spikes were required to induce persistent firing in neocortical interneurons (neocortex, 1821 ± 381 hippocampus, 792 ± 32), the resulting maximum persistent firing frequency was higher (neocortex, 123 ± 13 Hz hippocampus, 53 ± 2 Hz) and was reached more quickly (neocortex, 1.2 ± 0.5 sec from end of triggering stimulus hippocampus, 3.5 ± 0.2 sec), and the duration of persistent firing was shorter (neocortex, median 2.6 sec hippocampus, median 58 sec Supplementary Fig. 4a𠄾). These observations indicate that all aspects of persistent firing are more rapid in neocortex than in hippocampus.
In addition to step current injections, synaptic stimulation or sine wave current injections (mimicking theta oscillations) could also induce persistent firing (Supplementary Fig. 5). In EGFP-positive interneurons of Htr5b BAC transgenic mice, antidromic stimulation during cell-attached recording also elicited persistent firing, indicating that persistent firing is not an artifact of cytoplasmic washout during whole-cell recording. The induction of persistent firing using antidromic stimulation was performed in the presence of blockers for glutamate and GABA receptors (see Methods), indicating that activation of AMPA, NMDA, GABAA or GABAB receptors was not required for persistent firing (Supplementary Fig. 5). With all of these methods, multiple stimuli were required to induce persistent firing. After persistent firing ceased, the neuron could be stimulated again to produce another epoch of persistent firing (see Methods), indicating that persistent firing was not caused by a decline in cell heath or recording quality.
Persistent firing in response to natural spike trains
To determine whether persistent firing could occur in response to physiologically relevant spiking patterns, we stimulated these cells using spike trains that were acquired from in vivo recordings of hippocampal interneurons (see Methods for details). Both a low-frequency pattern from a perforant path-associated interneuron in an anesthetized rat (T. Klausberger, ref. 12, 5.8 Hz mean, Fig. 2a ) and a higher frequency pattern from a hippocampal interneuron in an awake rat (S. Layton and M. Wilson, unpublished, 33 Hz mean, Fig. 2b ) induced persistent firing efficiently ( Fig. 2c ). The high frequency pattern was the most effective at evoking persistent firing (step/pause 19/22, low freq. 16/22, high freq. 14/14 cells). The reliability of natural spike trains to elicit persistent firing suggests that persistent firing is not an artifact of excessive spiking.
In vivo firing patterns induce persistent firing. (a,b) Persistent firing evoked by low (a) and high (b) frequency in vivo firing patterns. Bottom left, expanded segment of the high frequency in vivo firing pattern and corresponding evoked spikes. Asterisks indicate spikes that have no corresponding stimulus and thus indicate the onset of persistent firing during the stimulus period. (c) Comparison of the fraction of cells that generated persistent firing with various stimulation protocols. Step/pause (n = 19) is the protocol described in Fig. 1c and Supplementary Fig. 1a low (n = 16) and high (n = 14) freq. refer to the in vivo firing patterns shown in a, and b, respectively. (d,e) The total number of evoked spikes needed to generate persistent firing showed no difference between the low and high freq. protocols, but both were less than the step/pause protocol. (d) Within cell comparisons (n = 10). (e) Grouped data comparisons (step/pause n = 19 low freq. n = 16, high freq. n = 14). (f,g) The latency to persistent firing was shortest for the high freq. protocol. (f) Within cell comparisons (n = 10). (g) Grouped data comparisons (step/pause n = 19 low freq. n = 16, high freq. n = 14). Latency to persistent firing was greatest using the step/pause protocol. All summary data consist of mean ± s.e.m. ***P < 0.001, **P < 0.01, *P < 0.05. All data are from Htr5b-EGFP-positive hippocampal interneurons near the SR-SLM border.
The number of spikes required to induce persistent firing was significantly less when using the low-frequency and high-frequency in vivo patterns compared to the step/pause protocol within the same cells, whereas the number of spikes required using the high and low frequency patterns were not different ( Fig. 2d,e ).
The latency to persistent firing (defined as the time from the first evoked spike to the first persistent firing spike) was significantly longer for the step/pause protocol than either the low-frequency or high frequency in vivo patterns ( Fig. 2f,g ). The latency was also significantly less with the high frequency than the low frequency in vivo pattern.
The effectiveness of the in vivo firing patterns is likely due to the absence of the long (9 sec) pauses that are present in the current-step protocol. The high-frequency in vivo firing protocol required only
20% fewer spikes than the low-frequency in vivo protocol, but induction occurred sooner (i.e., those spikes occurred in a much shorter period of time), suggesting the total number of evoked spikes is more important than the frequency of the evoked spikes for triggering persistent firing.
Persistent firing follows slow integration of spikes
Regardless of the stimulation method used, hundreds of evoked spikes were required to trigger persistent firing ( Fig. 2d𠄾 ) and these spikes were evoked over durations ranging from tens of seconds to minutes ( Fig. 2f–g ). These findings indicate that spikes can be integrated over long periods of time, consistent with a leaky integrator having a long decay time constant.
To quantify the nature of the integrator, we fit the data from the in vivo and step/pause firing patterns used for induction. Different data sets produced different optimal fits, but in all cases there was a threshold of 270 integrated spikes and a decay time constant of 50 seconds. This simple model implies the existence of a mechanism that encodes the firing history of the neuron with a time constant of more than a minute.
Persistent firing is initiated in the distal axon
In contrast to spiking evoked with somatic current injection, during persistent firing there was no envelope of depolarization in the somatic patch-clamp recording spikes arose abruptly from a membrane potential near rest ( Fig. 3a,b apparent action potential threshold .7 ± 0.3 mV). The mean action potential threshold for the initial nine seconds of persistent firing was .8 ± 0.5 mV compared to a mean holding potential of .8 mV. The apparent spike threshold was more depolarized after longer periods of persistent firing, but always remained about 20 mV below the threshold for current-evoked action potentials (Supplementary Table 1). This feature of persistent spikes was similar to that of spikes evoked by antidromic stimulation of the axon ( Fig. 3c,d ), suggesting that persistent firing originates in the axon. Phase plots revealed that antidromic and spontaneous spikes had two components: an initial component represented spiking in the axon and a second component that overlapped with the current-evoked spikes, indicative of a somato-dendritic spike that follows the initial, axonally initiated spike ( Fig. 3d ).
Full-sized action potentials and large and small spikelets during persistent firing match antidromic full and partial spikes. (a) Persistent firing with somatically evoked (e.g., black arrow) and persistent firing (e.g., green arrow) action potentials indicated. (b) Somatically evoked (black) and persistent firing (green) action potentials, peak aligned. (c) Antidromic (blue) and somatically evoked action potentials (black) from the same cell in (a), peak aligned, (d) Phase plot (dV dt 𢄡 vs. V) of action potentials from (b,c) (stimulus artifact eliminated). The numbers 1 and 2 on all phase plots indicate presumed axonal and somatic firing, respectively. (e) Spontaneous large spikelets during persistent firing (n = 6). (f) Expanded view (top) of large spikelets (brown) and a full-sized spike (green) taken from (e) (brown and green arrows). Phase plots (bottom) of a large spikelet (brown), evoked (black) and persistent firing action potentials (green). (g) Hyperpolarization in this cell revealed small spikelets.(h) Expanded view (top, left) of the spikelets in (g). Phase plots (bottom) of a small spikelet (brown), evoked (black) and persistent firing (green) action potentials. Expanded view (top, right) of the initial part of the phase plot. (i) Full action potential (green), large (black and blue) and small spikelets (brown) evoked by antidromic stimulation during somatic hyperpolarization to mV in the presence of glutamate and GABA receptor blockers. (j) Colored spikes from (i) overlaid and aligned by the stimulus artifacts. (k) Phase plot from the spikes in (j) (right) with expanded view (left). All data are from Htr5b-EGFP-positive hippocampal interneurons near the SR-SLM border.
In some recordings (n = 11), partial spikes (spikelets) were observed during persistent firing ( Fig. 3e Supplementary Fig. 4f). These spikelets overlapped with the first portion of the full-amplitude spikes, with the peak of the spikelets corresponding to an inflection on the rising phase seen in the full-amplitude spikes. This is seen more clearly in the phase plots of a spikelet, full-amplitude spike during persistent firing and an evoked somatic spike ( Fig. 3f ). Note that the phase plot of the evoked action potential (black) has one component with the same peak dV dt 𢄡 as the spikelet and a second component with a peak matching the spike during persistent firing. These observations suggest that the first component of each action potential during persistent firing is an axonal spike, which sometimes fails to evoke a somato-dendritic spike. In some cells (n = 3), spikelets were observed during somatic hyperpolarization ( Fig. 3g ). An expanded view of the initial part of the phase plot ( Fig. 3h ) again reveals an inflection point where the persistent firing action potential follows the phase plot of the spikelet. These spikelets were smaller than those observed without hyperpolarization, suggesting that they are caused by propagation failures at a more distal axonal location ( Fig. 3h ) than the failure point of the larger spikelets ( Fig. 3e,f ). The spikelets described here (i.e., presumed to be caused by failure of axonal action potential propagation to the soma) were easily distinguishable from other spikelets that appeared to be from spikes in cells connected by gap junctions (Supplementary Fig. 6).
Persistent firing continued during somatic hyperpolarization and the apparent spike threshold decreased as the soma was hyperpolarized ( Fig. 3g ), suggesting that the spikes are generated in an electrotonically remote location. In some cells, persistent firing appeared to cease during hyperpolarization of the soma (n = 11/21), but resumed without delay upon removal of the hyperpolarizing current (Supplementary Fig. 7). In these instances we are unable to distinguish between true cessation of firing and continued axonal spiking with failure of these spikes to invade the soma.
Spikelets were also observed in response to antidromic stimulation of the axon while hyperpolarizing the soma with current injection. In some cases, antidromic spikelets with two different amplitudes were observed in the same cell (n = 9 Fig. 3i–k ). Phase plots of these spikelets show that the large spikelet follows the initial component of the full action potential ( Fig. 3k ) in much the same way the large spikelet follows the full action potential during persistent firing shown in Fig. 3f . The phase plot also shows the small antidromic spikelet overlapping the initial component of the large spikelet and full action potential, suggesting that these small events give rise to the larger ones, as observed during persistent firing.
Using a simple computational model of a branching axon attached to a soma, we simulated both small- and large-amplitude spikelets, as well as full-amplitude spikes, by depolarizing a branch of the axon during somatic hyperpolarization. Large-amplitude spikelets corresponded to failure of the action potential to invade the soma, while small-amplitude spikelets corresponded to failures at the axon branches, 40 μm from the soma ( Fig. 4a𠄼 Supplementary Movie 1). Similar results were obtained with a full morphological model of a branching axonal arborization ( Fig. 4d𠄿 Supplementary Movie 2).
Simulation of small and large spikelets indicates failure of antidromic action potentials at different locations along the axon. (a) Morphology of a stylized interneuron model, with a spherical soma connected to a primary axon with five side branches. (b) Somatic voltage trace in the stylized model as a result of distal axonal depolarization (960 μm from soma) during simultaneous somatic hyperpolarization. The resulting antidromic action potentials occurred in a repeating pattern consisting of a full action potential (green), an antidromic action potential that fails at the soma (blue), and three small spikelets (red only one shown) corresponding to action potential failure at an axonal branch point. (c) Phase plot of traces from (b). Inset shows expanded view. (d) Morphology of a fully reconstructed interneuron with its cell body near the SR-SLM border, showing soma and dendrites (blue), axon (red) and locations of the axonal and somatic stimulating and recording electrodes. Inset: Expanded view, showing the two different points at which antidromic axonal action potentials fail. (e) Voltage trace in the full morphological model as a result of distal axonal depolarization (325 μm from the soma) during simultaneous somatic hyperpolarization. Antidromic action potentials were generated and produced a repeating somatic voltage pattern consisting of a full action potential (green), an antidromic action potential that fails at the soma (blue), and an antidromic action potential that fails at an axonal branch point (brown). (f) Phase plot of traces from (e). Inset shows expanded view.
Persistent firing does not require somatic depolarization
To further test the hypothesis that persistent firing is generated in the axon, we induced it by delivering antidromic stimuli repeatedly. Antidromic stimulation was applied in the dentate gyrus, a region frequently containing branches of the axon, but never the dendrites of the CA1 interneurons we targeted. These experiments were also performed in the presence of glutamate and GABA receptor blockers in order to prevent synaptic activation of dendrites (see Methods). When antidromic stimulation was performed repeatedly (increasing the frequency of stimuli in subsequent sweeps), persistent firing could be induced, even while holding the somatic membrane potential at a hyperpolarized level that reduced or eliminated somatic spiking during the antidromic stimulation ( Fig. 5a,b n = 5). Under these conditions, small-amplitude spikelets were recorded at the soma in response to most antidromic stimuli, and represented propagation failures of antidromic evoked spikes that looked similar to spikelets during persistent firing ( Fig. 3e–h ). Persistent action potential firing was nevertheless observed after both the antidromic stimulus and the hyperpolarizing current injection ceased ( Fig. 5b ). These results support the hypothesis that persistent firing is generated in the distal axon and that it can be generated even in the absence of depolarization of the dendrites, soma, or proximal axon.
Persistent firing induced by antidromic stimulation and inter-cellular signaling. (a) Diagram depicting recording setup (axon red, dendrites blue). For antidromic stimulation, the stimulating electrode was placed in the molecular layer of the dentate gyrus (DG) to activate only axonal projections. (b) Antidromic stimulation of the axon during simultaneous somatic hyperpolarization also evoked persistent firing (in the presence of glutamate and GABA receptor blockers see online Methods). The inset shows failed spikes during antidromic stimulation. The number of stimuli was increased by two during each successive stimulus until persistent firing occurred. Persistent firing was reliably induced in this way (n = 5). (c) Illustration of paired recording set-up: step current injections were delivered to cell 1 only. Interneurons near the SR-SLM border and within the SR were targeted. (d) Persistent firing was induced in the unstimulated cell and occurred before persistent firing was induced in the stimulated cell. No electrical coupling was observed between the pairs. In total, 19 Htr5b-EGFP-positive pairs were studied with 3 showing this type of inter-cellular induction of persistent firing.
To test for cell coupling during persistent firing, we recorded from 19 pairs of EGFP-positive hippocampal interneurons ( Fig. 5c ). None of these pairs exhibited obvious chemical synaptic coupling electrical coupling was observed in 6/19 pairs. To induce persistent firing, only one of the two cells was stimulated with step current injections. In 16/19 cases, persistent firing was only observed in the stimulated neuron in the other three pairs, persistent firing was induced in the unstimulated neuron ( Fig. 5d ). None of these three pairs exhibited direct electrical coupling. In two of these three pairs, persistent firing developed in the unstimulated neuron but not in the stimulated neuron ( Fig. 5d ). In the third pair, persistent firing began in the stimulated neuron first, then stopped, followed by persistent firing in the unstimulated neuron. In all three pairs, the same behavior recurred when the same stimulus was delivered again, indicating that the persistent firing was triggered by the stimulus. In all of our single-cell recordings (n = 274), we never saw persistent firing develop spontaneously. Thus, the observation of persistent firing in 3/19 unstimulated cells is a highly statistically significant indication that persistent firing can be induced by stimulating another cell (see Methods for details). These results are consistent with a form of inter-cellular signaling that promotes the induction of persistent firing in a network of sparsely connected interneurons.
Clues regarding the mechanisms of persistent firing
Elucidating the mechanisms responsible for persistent firing will be complex, because several questions must be addressed: What mechanisms allow hundreds of action potentials to be integrated on a timescale of tens of seconds to minutes? How is this integrated signal detected by more than just the stimulated neuron? What conductances are modulated to depolarize the axon and generate persistent firing? We made two important observations that will facilitate future studies of these mechanistic questions.
First, we found that lowering extracellular Ca 2+ did not prevent persistent firing or affect the number of spikes needed to induce it ( Fig. 6a𠄼 n = 20 for 0, 0.5 and 1 mM Ca 2+ ). This result suggests that neither Ca 2+ -dependent exocytosis nor a Ca 2+ conductance is likely to be required for persistent firing. However, lower Ca 2+ concentrations did lead to longer-lasting persistent firing, suggesting that Ca 2+ entry may participate in the termination of persistent firing.
Calcium effects on persistent firing. (a) Recordings from an Htr5b-EGFP-positive hippocampal interneuron in normal (top 2 mM) and low (bottom 0.5 mM) Ca 2+ ACSF. Note the firing lasts dramatically longer in low Ca 2+ than in normal ACSF. (b) Bar graph showing the number of evoked spikes required to induce persistent firing remains unchanged in low Ca 2+ conditions (all data normalized to the 2 mM condition in the same cells 1 mM n = 9, 0.5 mM n = 11 and 0 mM n = 10). Increasing the Ca 2+ concentration to 5 mM slightly reduced the number of evoked spikes required to induce persistent firing (n = 4). (c) The duration of persistent firing is significantly increased in low Ca 2+ (0.5 mM and 0 mM) and reduced in high Ca 2+ (5 mM). All statistics are paired-sample comparisons relative to 2 mM Ca 2+ in the same cell, * P < 0.05. All summary data are mean ± s.e.m. All data are from Htr5b-EGFP-positive hippocampal interneurons near the SR-SLM border.
Second, we found that two gap-junction-inhibiting drugs (mefloquine and carbenoxelone) prevented the induction of persistent firing ( Fig. 7a,b ). In these experiments, PF was not induced in the presence of either drug, even when the number of evoked action potentials far exceeded that required to induce persistent firing in the same cells prior to drug application ( Fig. 7c,d n = 10). Although the action of these drugs was not reversed, in the absence of gap junction blockers we were able to induce persistent firing repeatedly in every cell where we attempted to do so, including 101 cells where persistent firing was induced five times or more. These experiments indicate that the effects of the gap-junction blockers were not an artifact of the long time required for their action. These gap junction blockers are known to have some side effects 13 , 14 , so the results must be interpreted with caution, but the common action of both drugs implicates gap junctions in either the integration of action potentials leading up to persistent firing or the generation of distal axonal action potentials during persistent firing. Hippocampal and neocortical interneurons are often connected by gap junctions 15 , but in our paired recordings from EGFP-labeled interneurons, direct electrical coupling was usually not observed, including in the three pairs where we observed persistent firing in the unstimulated neuron. For this reason, the relevant gap junctions may not be between the somata or dendrites. Rather, they could be located between axons 16 or between glial cells that may participate in persistent firing in some way 17 - 19 . Much additional work will be required to elucidate the mechanisms of this form of persistent firing, including investigation of the involvement of gap junctions.
Gap junction blockers inhibit persistent firing. (a) Mefloquine (25 μM) and (b) Carbenoxolone (500 μM) were bath applied after three trials of persistent firing (sequential trial iteration indicated with number to the left of the trace) induction. Persistent firing was induced approximately once every 7 min (depending on how many spikes were required in each trial). The numbers above the evoked spikes indicate the total number of evoked action potentials for that trial. (c) The total number of evoked action potentials required to evoke persistent firing is plotted against the trial number (for 6 cells). 25 μM Mefloquine was added to the bath after the third trial in each cell. In 5 out of the 6 cells PF was not induced in the presence of mefloquine (represented by the red triangles indicating the maximum number of evoked spikes that was reached on that trial). (c) 500 μM Carbenoxolone had a similar effect, preventing persistent firing in 4 out of 4 cells. All data are from Htr5b-EGFP-positive hippocampal interneurons near the SR-SLM border.
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