Biophysical Factors that Promote Mechanically-Induced Action Potentials in Neocortical and Hippocampal Pyramidal Neurons

In hippocampal pyramidal neurons, voltage-gated Ca2+ channels open in response to action potentials. This results in elevations in the intracellular concentration of Ca2+ that are maximal in the proximal apical dendrites and decrease rapidly with distance from the soma. The control of these action potential-evoked Ca2+ elevations is critical for the regulation of hippocampal neuronal activity. As part of Ca2+ signaling microdomains, small-conductance Ca2+-activated K+ (SK) channels have been shown to modulate the amplitude and duration of intracellular Ca2+ signals by feedback regulation of synaptically activated Ca2+ sources in small distal dendrites and dendritic spines, thus affecting synaptic plasticity in the hippocampus. In this study, we investigated the effect of the activation of SK channels on Ca2+ transients specifically induced by action potentials in the proximal processes of hippocampal pyramidal neurons. Our results, obtained by using selective SK channel blockers and enhancers, show that SK channels act in a feedback loop, in which their activation by Ca2+ entering mainly through L-type voltage-gated Ca2+ channels leads to a reduction in the subsequent dendritic influx of Ca2+. This underscores a new role of SK channels in the proximal apical dendrite of hippocampal pyramidal neurons.

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Extracellular waveforms reveal an axonal origin of spikelets in pyramidal neurons

Journal of Neurophysiology ◽

10.1152/jn.00463.2017 ◽

2018 ◽

Vol 120 (4) ◽

pp. 1484-1495 ◽

Cited By ~ 1

Author(s):

Martina Michalikova ◽

Michiel W. H. Remme ◽

Richard Kempter

Keyword(s):

Experimental Data ◽

Action Potential ◽

Single Cell ◽

Action Potentials ◽

Pyramidal Neurons ◽

Hippocampal Pyramidal Neurons ◽

Coupled Cells ◽

A Cell ◽

Cell Firing

Spikelets are small spike-like membrane depolarizations measured at the soma whose origin in pyramidal neurons is still unresolved. We investigated the mechanism of spikelet generation using detailed models of pyramidal neurons. We simulated extracellular waveforms associated with action potentials and spikelets and compared these with experimental data obtained by Chorev and Brecht ( J Neurophysiol 108: 1584–1593, 2012) from hippocampal pyramidal neurons in vivo. We considered spikelets originating in the axon of a single cell as well as spikelets generated in two cells coupled with gap junctions. We found that in both cases the experimental data can be explained by an axonal origin of spikelets: in the single-cell case, action potentials are generated in the axon but fail to activate the soma. Such spikelets can be evoked by dendritic input. Alternatively, spikelets resulting from axoaxonal gap junction coupling with a large (greater than several hundred μm) distance between the somata of the coupled cells are also consistent with the data. Our results demonstrate that a cell firing a somatic spikelet generates a detectable extracellular potential that is different from the action potential-correlated extracellular waveform generated by the same cell and recorded at the same location. This, together with the absence of a refractory period between action potentials and spikelets, implies that spikelets and action potentials generated in one cell may easily get misclassified in extracellular recordings as two different cells, albeit they both constitute the output of a single pyramidal neuron. NEW & NOTEWORTHY We addressed the origin of spikelets, using compartmental models of pyramidal neurons. Comparing our simulation results with published extracellular spikelet recordings revealed an axonal origin of spikelets. Our results imply that action potential- and spikelet-associated extracellular waveforms may easily get misclassified as two different cells, albeit they both constitute the output of a single pyramidal cell.

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Single mechanically-gated cation channel currents can trigger action potentials in neocortical and hippocampal pyramidal neurons

Brain Research ◽

10.1016/j.brainres.2015.02.051 ◽

2015 ◽

Vol 1608 ◽

pp. 1-13 ◽

Cited By ~ 10

Author(s):

Yury A. Nikolaev ◽

Peter J. Dosen ◽

Derek R. Laver ◽

Dirk F. van Helden ◽

Owen P. Hamill

Keyword(s):

Action Potentials ◽

Pyramidal Neurons ◽

Cation Channel ◽

Hippocampal Pyramidal Neurons ◽

Channel Currents ◽

Trigger Action

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Different Ca2+ channels in soma and dendrites of hippocampal pyramidal neurons mediate spike-induced Ca2+ influx

Journal of Neurophysiology ◽

10.1152/jn.1995.73.6.2553 ◽

1995 ◽

Vol 73 (6) ◽

pp. 2553-2557 ◽

Cited By ~ 152

Author(s):

B. R. Christie ◽

L. S. Eliot ◽

K. Ito ◽

H. Miyakawa ◽

D. Johnston

Keyword(s):

Pyramidal Cell ◽

Action Potentials ◽

Pyramidal Neurons ◽

High Threshold ◽

Intracellular Recordings ◽

Hippocampal Pyramidal Neurons ◽

Low Threshold ◽

Dependent Processes ◽

Cell Somata ◽

Ca2 Channels

1. Intracellular recordings, in conjunction with fura-2 fluorescence imaging, were used to evaluate the contribution of the different Ca2+ channel subtypes to the Ca2+ influx induced by back-propagating trains of action potentials. High-threshold channels contributed mainly to Ca2+ influx in pyramidal cell somata and proximal dendrites, whereas low-threshold and other Ni(2+)-sensitive channels played a greater role in more distal dendritic signaling. These data suggest that the different Ca2+ channel types participate in distinct physiological functions; low-threshold channels likely play a greater role in dendritic integration, whereas high-threshold channels are more important for somatic Ca(2+)-dependent processes.

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A model for dendritic Ca2+ accumulation in hippocampal pyramidal neurons based on fluorescence imaging measurements

Journal of Neurophysiology ◽

10.1152/jn.1994.71.3.1065 ◽

1994 ◽

Vol 71 (3) ◽

pp. 1065-1077 ◽

Cited By ~ 88

Author(s):

D. B. Jaffe ◽

W. N. Ross ◽

J. E. Lisman ◽

N. Lasser-Ross ◽

H. Miyakawa ◽

...

Keyword(s):

Fluorescence Imaging ◽

Action Potentials ◽

Hippocampal Neurons ◽

Pyramidal Neurons ◽

Na Channels ◽

Hippocampal Pyramidal Neurons ◽

K Channels ◽

Voltage Gated ◽

Synaptic Potentials ◽

Ca2 Channels

1. High-speed fluorescence imaging was used to measure intracellular Ca2+ concentration ([Ca2+]i) changes in hippocampal neurons injected with the Ca(2+)-sensitive indicator fura-2 during intrasomatic and synaptic stimulation. The results of these experiments were used to construct a biophysical model of [Ca2+]i dynamics in hippocampal neurons. 2. A compartmental model of a pyramidal neuron was constructed incorporating published passive membrane properties of these cells, three types of voltage-gated Ca2+ channels characterized from adult hippocampal neurons, voltage-gated Na+ and K+ currents, and mechanisms for Ca2+ buffering and extrusion. 3. In hippocampal pyramidal neurons imaging of Na+ entry during electrical activity suggests that Na+ channels, at least in sufficient density to sustain action potentials, are localized in the soma and the proximal part of the apical dendritic tree. The model, which incorporates this distribution, demonstrates that action potentials attenuate steeply in passive distal dendritic compartments or distal dendritic compartments containing Ca2+ and K+ channels. This attenuation was affected by intracellular resistivity but not membrane resistivity. 4. Consistent with fluorescence imaging experiments, a non-uniform distribution of Ca2+ accumulation was generated by Ca2+ entry through voltage-gated Ca2+ channels opened by decrementally propagating Na+ action potentials. Consequently, the largest increases in [C2+]i were produced in the proximal dendrites. Distal voltage-gated Ca2+ currents were activated by broad, almost isopotential action potentials produced by reducing the overall density of K+ channels. 5. Simulations of subthreshold synaptic stimulation produced dendritic Ca2+ entry by the activation of voltage-gated Ca2+ channels. In the model these Ca2+ signals were localized near the site of synaptic input because of the attenuation of synaptic potentials with distance from the site of origin and the steep voltage-dependence of Ca2+ channel activation. 6. These simulations support the hypotheses generated from experimental evidence regarding the differential distribution of voltage-gated Ca2+ and Na+ channels in hippocampal neurons and the resulting voltage-gated Ca2+ accumulation from action and synaptic potentials.

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In vivo dual intra- and extracellular recordings suggest bidirectional coupling between CA1 pyramidal neurons

Journal of Neurophysiology ◽

10.1152/jn.01115.2011 ◽

2012 ◽

Vol 108 (6) ◽

pp. 1584-1593 ◽

Cited By ~ 22

Author(s):

Edith Chorev ◽

Michael Brecht

Keyword(s):

Pyramidal Neuron ◽

Action Potentials ◽

Pyramidal Neurons ◽

Hippocampal Pyramidal Neurons ◽

Voltage Dependent ◽

Dendritic Spikes ◽

Discharge Patterns ◽

Ca1 Pyramidal Neuron ◽

Neighboring Neuron

Spikelets, small spikelike membrane potential deflections, are prominent in the activity of hippocampal pyramidal neurons in vivo. The origin of spikelets is still a source of much controversy. Somatically recorded spikelets have been postulated to originate from dendritic spikes, ectopic spikes, or spikes in an electrically coupled neuron. To differentiate between the different proposed mechanisms we used a dual recording approach in which we simultaneously recorded the intracellular activity of one CA1 pyramidal neuron and the extracellular activity in its vicinity, thus monitoring extracellularly the activity of both the intracellularly recorded cell as well as other units in its surroundings. Spikelets were observed in a quarter of our recordings ( n = 36). In eight of these nine recordings a second extracellular unit fired in correlation with spikelet occurrences. This observation is consistent with the idea that the spikelets reflect action potentials of electrically coupled nearby neurons. The extracellular spikes of these secondary units preceded the onset of spikelets. While the intracellular spikelet amplitude was voltage dependent, the simultaneously recorded extracellular unit remained unchanged. Spikelets often triggered action potentials in neurons, resulting in a characteristic 1- to 2-ms delay between spikelet onset and firing. Here we show that this relationship is bidirectional, with spikes being triggered by and also triggering spikelets. Secondary units, coupled to pyramidal neurons, showed discharge patterns similar to the recorded pyramidal neuron. These findings suggest that spikelets reflect spikes in an electrically coupled neighboring neuron, most likely of pyramidal cell type. Such coupling might contribute to the synchronization of pyramidal neurons with millisecond precision.

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Ca2+ Channels Involved in the Generation of the Slow Afterhyperpolarization in Cultured Rat Hippocampal Pyramidal Neurons

Journal of Neurophysiology ◽

10.1152/jn.2000.83.5.2554 ◽

2000 ◽

Vol 83 (5) ◽

pp. 2554-2561 ◽

Cited By ~ 61

Author(s):

M. Shah ◽

D. G. Haylett

Keyword(s):

Calcium Channels ◽

Action Potentials ◽

Calcium Release ◽

Pyramidal Neurons ◽

Pyramidal Cells ◽

Isolated Cells ◽

Hippocampal Pyramidal Neurons ◽

Calcium Induced Calcium Release ◽

Ca2 Channels ◽

Hippocampal Pyramidal Cells

The advantages of using isolated cells have led us to develop short-term cultures of hippocampal pyramidal cells, which retain many of the properties of cells in acute preparations and in particular the ability to generate afterhyperpolarizations after a train of action potentials. Using perforated-patch recordings, both medium and slow afterhyperpolarization currents (m I AHP and s I AHP, respectively) could be obtained from pyramidal cells that were cultured for 8–15 days. The s I AHP demonstrated the kinetics and pharmacologic characteristics reported for pyramidal cells in slices. In addition to confirming the insensitivity to 100 nM apamin and 1 mM TEA, we have shown that the s I AHP is also insensitive to 100 nM charybdotoxin but is inhibited by 100 μMd-tubocurarine. Concentrations of nifedipine (10 μM) and nimodipine (3 μM) that maximally inhibit L-type calcium channels reduced the s I AHP by 30 and 50%, respectively. However, higher concentrations of nimodipine (10 μM) abolished the s I AHP, which can be partially explained by an effect on action potentials. Both nifedipine and nimodipine at maximal concentrations were found to reduce the HVA calcium current in freshly dissociated neurons to the same extent. The N-type calcium channel inhibitor, ω-conotoxin GVIA (100 nM), irreversibly inhibited the s I AHP by 37%. Together, ω-conotoxin (100 nM) and nifedipine (10 μM) inhibited the s I AHP by 70%. 10 μM ryanodine also reduced the s I AHP by 30%, suggesting a role for calcium-induced calcium release. It is concluded that activation of the s I AHP in cultured hippocampal pyramidal cells is mediated by a rise in intracellular calcium involving multiple pathways and not just entry via L-type calcium channels.

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