Layer-Specific Generation and Propagation of Seizures in Slices of Developing Neocortex: Role of Excitatory GABAergic Synapses

2008 ◽  
Vol 100 (2) ◽  
pp. 620-628 ◽  
Author(s):  
Sylvain Rheims ◽  
Alfonso Represa ◽  
Yehezkel Ben-Ari ◽  
Yuri Zilberter
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Neonatal Period ◽  
Pyramidal Cells ◽  
Resting Potential ◽  
Nmda Channel ◽  
Gabaergic Synapses ◽  
Developing Neocortex ◽  
Excitatory Gaba

The neonatal period is critical for seizure susceptibility, and neocortical networks are central in infantile epilepsies. We report that application of 4-aminopyridine (4-AP) to immature (P6–P9) neocortical slices generates layer-specific interictal seizures (IISs) that transform after recurrent seizures to ictal seizures (ISs). During IISs, cell-attached recordings show action potentials in interneurons and pyramidal cells in L5/6 and interneurons but not pyramidal neurons in L2/3. However, L2/3 pyramidal neurons also fire during ISs. Using single N-methyl-d-aspartate (NMDA) channel recordings for measuring the cell resting potential ( Em), we show that transition from IISs to ISs is associated with a gradual Em depolarization of L2/3 and L5/6 pyramidal neurons that enhances their excitability. Bumetanide, a NKCC1 co-transporter antagonist, inhibits generation of IISs and prevents their transformation to ISs, indicating the role excitatory GABA in epilepsies. Therefore deep layer neurons are more susceptible to seizures than superficial ones. The initiating phase of seizures is characterized by IISs generated in L5/6 and supported by activation of both L5/6 interneurons and pyramidal cells. IISs propagate to L2/3 via activation of L2/3 interneurons but not pyramidal cells, which are mostly quiescent at this phase. In superficial layers, a persistent increase in excitability of pyramidal neurons caused by Em depolarization is associated with a transition from largely confined GABAergic IIS to ictal events that entrain the entire neocortex.

Dichotomy of Action-Potential Backpropagation in CA1 Pyramidal Neuron Dendrites

2001 ◽  
Vol 86 (6) ◽  
pp. 2998-3010 ◽  
Author(s):  
Nace L. Golding ◽  
William L. Kath ◽  
Nelson Spruston
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Synaptic Activity ◽  
Resting Potential ◽  
Model Parameters ◽  
Voltage Sensitivity ◽  
Whole Cell ◽  
Ca1 Pyramidal Neurons ◽  
Whole Cell Recordings

In hippocampal CA1 pyramidal neurons, action potentials are typically initiated in the axon and backpropagate into the dendrites, shaping the integration of synaptic activity and influencing the induction of synaptic plasticity. Despite previous reports describing action-potential propagation in the proximal apical dendrites, the extent to which action potentials invade the distal dendrites of CA1 pyramidal neurons remains controversial. Using paired somatic and dendritic whole cell recordings, we find that in the dendrites proximal to 280 μm from the soma, single backpropagating action potentials exhibit <50% attenuation from their amplitude in the soma. However, in dendritic recordings distal to 300 μm from the soma, action potentials in most cells backpropagated either strongly (26–42% attenuation; n = 9/20) or weakly (71–87% attenuation; n = 10/20) with only one cell exhibiting an intermediate value (45% attenuation). In experiments combining dual somatic and dendritic whole cell recordings with calcium imaging, the amount of calcium influx triggered by backpropagating action potentials was correlated with the extent of action-potential invasion of the distal dendrites. Quantitative morphometric analyses revealed that the dichotomy in action-potential backpropagation occurred in the presence of only subtle differences in either the diameter of the primary apical dendrite or branching pattern. In addition, action-potential backpropagation was not dependent on a number of electrophysiological parameters (input resistance, resting potential, voltage sensitivity of dendritic spike amplitude). There was, however, a striking correlation of the shape of the action potential at the soma with its amplitude in the dendrite; larger, faster-rising, and narrower somatic action potentials exhibited more attenuation in the distal dendrites (300–410 μm from the soma). Simple compartmental models of CA1 pyramidal neurons revealed that a dichotomy in action-potential backpropagation could be generated in response to subtle manipulations of the distribution of either sodium or potassium channels in the dendrites. Backpropagation efficacy could also be influenced by local alterations in dendritic side branches, but these effects were highly sensitive to model parameters. Based on these findings, we hypothesize that the observed dichotomy in dendritic action-potential amplitude is conferred primarily by differences in the distribution, density, or modulatory state of voltage-gated channels along the somatodendritic axis.

scholarly journals Bayesian modeling of BAC firing as a mechanism for apical amplification in neocortical pyramidal neurons

2019 ◽  
Author(s):  
Jim W. Kay ◽  
W. A. Phillips ◽  
Jaan Aru ◽  
Bruce P. Graham ◽  
Matthew E. Larkum
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Single Site ◽  
Biophysical Model ◽  
Cellular Mechanisms ◽  
Context Sensitive ◽  
Dendritic Shaft ◽  
Current Task ◽  
Integration Sites

AbstractPyramidal cells in layer 5 of the neocortex have two distinct integration sites. These cells integrate inputs to basal dendrites in the soma while integrating inputs to the tuft in a site at the top of the apical trunk. The two sites communicate by action potentials that backpropagate to the apical site and by backpropagation-activated calcium spikes (BAC firing) that travel from the apical to the somatic site. Six key messages arise from the probabilistic information-theoretic analyses of BAC firing presented here. First, we suggest that pyramidal neurons with BAC firing could convert the odds in favour of the presence of a feature given the basal data into the odds in favour of the presence of a feature given the basal data and the apical input, by a simple Bayesian calculation. Second, the strength of the cell’s response to basal input can be amplified when relevant to the current context, as specified by the apical input, without corrupting the message that it sends. Third, these analyses show rigorously how this apical amplification depends upon communication between the sites. Fourth, we use data on action potentials from a very detailed multi-compartmental biophysical model to study our general model in a more realistic setting, and demonstrate that it describes the data well. Fifth, this form of BAC firing meets criteria for distinguishing modulatory from driving interactions that have been specified using recent definitions of multivariate mutual information. Sixth, our general decomposition can be extended to cases where, instead of being purely driving or purely amplifying, apical and basal inputs can be partly driving and partly amplifying to various extents. These conclusions imply that an advance beyond the assumption of a single site of integration within pyramidal cells is needed, and suggest that the evolutionary success of neocortex may depend upon the cellular mechanisms of context-sensitive selective amplification hypothesized here.Author summaryThe cerebral cortex has a key role in conscious perception, thought, and action, and is predominantly composed of a particular kind of neuron: the pyramidal cells. The distinct shape of the pyramidal neuron with a long dendritic shaft separating two regions of profuse dendrites allows them to integrate inputs to the two regions separately and combine the results non-linearly to produce output. Here we show how inputs to this more distant site strengthen the cell’s output when it is relevant to the current task and environment. By showing that such neurons have capabilities that transcend those of neurons with the single site of integration assumed by many neuroscientists, this ‘splitting of the neuronal atom’ offers a radically new viewpoint from which to understand the evolution of the cortex and some of its many pathologies. This also suggests that approaches to artificial intelligence using neural networks might come closer to something analogous to real intelligence, if, instead of basing them on processing elements with a single site of integration, they were based on elements with two sites, as in cortex.

Characterization of an early afterhyperpolarization after a brief train of action potentials in rat hippocampal neurons in vitro

1990 ◽  
Vol 63 (1) ◽  
pp. 72-81 ◽  
Author(s):  
A. Williamson ◽  
B. E. Alger
Keyword(s):  
Action Potentials ◽  
Hippocampal Neurons ◽  
Pyramidal Cells ◽  
Chloride Ions ◽  
Membrane Potentials ◽  
Resting Potential ◽  
K Channel ◽  
Delayed Rectifier ◽  
Extracellular Potassium

1. In rat hippocampal pyramidal cells in vitro, a brief train of action potentials elicited by direct depolarizing current pulses injected through an intracellular recording electrode is followed by a medium-duration afterhyperpolarization (mAHP) and a longer, slow AHP. We studied the mAHP with the use of current-clamp techniques in the presence of dibutyryl cyclic adenosine 3',5'-monophosphate (cAMP) to block the slow AHP and isolate the mAHP. 2. The mAHP evoked at hyperpolarized membrane potentials was complicated by a potential generated by the anomalous rectifier current, IQ. The mAHP is insensitive to chloride ions (Cl-), whereas it is sensitive to the extracellular potassium concentration ([K+]o). 3. At slightly depolarized levels, the mAHP is partially Ca2+ dependent, being enhanced by increased [Ca2+]o and BAY K 8644 and depressed by decreased [Ca2+]o, nifedipine, and Cd2+. The Ca2(+)-dependent component of the mAHP was also reduced by 100 microM tetraethylammonium (TEA) and charybdotoxin (CTX), suggesting it is mediated by the voltage- and Ca2(+)-dependent K+ current, IC. 4. Most of the Ca2(+)-independent mAHP was blocked by carbachol, implying that IM plays a major role. In a few cells, a small Ca2(+)- and carbachol-insensitive mAHP component was detectable, and this component was blocked by 10 mM TEA, suggesting it was mediated by the delayed rectifier current, IK. The K+ channel antagonist 4-aminopyridine (4-AP, 500 microM) did not reduce the mAHP. 5. We infer that the mAHP is a complex potential due either to IQ or to the combined effects of IM and IC. The contributions of each current depend on the recording conditions, with IC playing a role when the cells are activated from depolarized potentials and IM dominating at the usual resting potential. IQ is principally responsible for the mAHP recorded at hyperpolarized membrane potentials.

Effect of sodium deficiency of the action potential of the smooth muscle of ureter

1964 ◽  
Vol 206 (1) ◽  
pp. 205-210 ◽  
Author(s):  
Makoto Kobayashi ◽  
Hiroshi Irisawa
Keyword(s):  
Smooth Muscle ◽  
Action Potential ◽  
Action Potentials ◽  
Essential Role ◽  
Choline Chloride ◽  
Resting Potential ◽  
Sodium Deficiency ◽  
Repolarization Phase ◽  
Extracellular Sodium

Action potentials of the smooth muscle of cat ureter were studied by using ultramicroelectrodes. Among 193 penetrations, the resting potential averaged 45 mv and the amplitude of action potential 32 mv. In four instances a slight overshoot was recorded. Action potential consisted of a relatively rapid rising phase followed by a slow repolarization phase, and its duration was about 0.3 sec. Effects of sodium deficiency on action potential were studied by using three different sodium substitutes. Both the height and the rising rate of action potential decreased as the concentration of extracellular sodium was reduced, indicating that the action potential of ureter muscle can be explained on the basis of sodium theory. The duration of the action potential was prolonged when sucrose or choline chloride was used as a sodium substitute; on the other hand, it shortened when tris chloride was employed. The essential role of sodium ions in the development of the action potential in ureter muscle is discussed.

Axon terminal hyperexcitability associated with epileptogenesis in vitro. I. Origin of ectopic spikes

1993 ◽  
Vol 70 (3) ◽  
pp. 961-975 ◽  
Author(s):  
S. F. Stasheff ◽  
M. Hines ◽  
W. A. Wilson
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Model Neuron ◽  
Extracellular Recording ◽  
Pyramidal Cells ◽  
Initiation Site ◽  
Electrographic Seizures ◽  
Ca3 Pyramidal Cells

1. Intracellular and extracellular recording techniques were used to study the increase in ectopic (i.e., nonsomatic) action-potential generation occurring among CA3 pyramidal cells during the kindling-like induction of electrographic seizures (EGSs) in this subpopulation of the hippocampal slice. Kindling-like stimulus trains (60 Hz, 2 s) were delivered to s. radiatum of CA3 at 10-min intervals. As EGSs developed, the frequency of ectopic firing increased markedly (by 10.33 +/- 3.29 spikes/min, mean +/- SE, P << 0.01). Several methods were applied to determine the initiation site for these action potentials within the cell (axons vs. dendrites). 2. Collision tests were conducted between known antidromic and orthodromic action potentials in CA3 cells to determine the critical period, c, for collision. Attempts were then made to collide ectopic spikes with known antidromic action potentials. At intervals less than c, ectopic spikes failed to collide with antidromic ones, in 5 of 10 cases. In these cells, this clearly indicates that the ectopic spikes were themselves of axonal origin. In the remaining five cases, ectopic spikes collided with antidromic action potentials at intervals approximately equal to c, most likely because of interactions within the complex system of recurrent axon collaterals in CA3. 3. Action potentials of CA3 pyramidal cells were simulated with the use of a compartmental computer model, NEURON. These simulations were based on prior models of CA3 pyramidal neurons and of the motoneuron action potential. Simulated action potentials generated in axonal compartments possessed a prominent inflection on their rising phase (IS-SD break), which was difficult to appreciate in those spikes generated in somatic or dendritic compartments. 4. An analysis of action potentials recorded experimentally from CA3 pyramidal cells also showed that antidromic spikes possess a prominent IS-SD break that is not present in orthodromic spikes. In addition to identified antidromic action potentials, ectopic spikes also possess such an inflection. Together with the predictions of computer simulations, this analysis also indicates that ectopic spikes originate in the axons of CA3 cells. 5. Tetrodotoxin (TTX, 50 microM) was locally applied by pressure injection while monitoring ectopic spike activity. Localized application of TTX to regions of the slice that could include the axons but not the dendrites of recorded cells abolished or markedly reduced the frequency of ectopic spikes (n = 5), further confirming the hypothesis that these action potentials arise from CA3 axons.(ABSTRACT TRUNCATED AT 400 WORDS)

Development of Intrinsic Properties and Excitability of Layer 2/3 Pyramidal Neurons During a Critical Period for Sensory Maps in Rat Barrel Cortex

2004 ◽  
Vol 92 (1) ◽  
pp. 144-156 ◽  
Author(s):  
Miguel Maravall ◽  
Edward A. Stern ◽  
Karel Svoboda
Keyword(s):  
Critical Period ◽  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Pyramidal Cells ◽  
Membrane Properties ◽  
Sensory Maps ◽  
Layer 2 ◽  
Whole Cell Recordings ◽  
Passive Membrane Properties

The development of layer 2/3 sensory maps in rat barrel cortex (BC) is experience dependent with a critical period around postnatal days (PND) 10–14. The role of intrinsic response properties of neurons in this plasticity has not been investigated. Here we characterize the development of BC layer 2/3 intrinsic responses to identify possible sites of plasticity. Whole cell recordings were performed on pyramidal cells in acute BC slices from control and deprived rats, over ages spanning the critical period (PND 12, 14, and 17). Vibrissa trimming began at PND 9. Spiking behavior changed from phasic (more spike frequency adaptation) to regular (less adaptation) with age, such that the number of action potentials per stimulus increased. Changes in spiking properties were related to the strength of a slow Ca2+-dependent afterhyperpolarization. Maturation of the spiking properties of layer 2/3 pyramidal neurons coincided with the close of the critical period and was delayed by deprivation. Other measures of excitability, including I-f curves and passive membrane properties, were affected by development but unaffected by whisker deprivation.

scholarly journals Probing the polarity of spontaneous perisomatic GABAergic synaptic transmission during epileptogenesis in the mouse CA3 circuit in vivo

2019 ◽  
Author(s):  
Olivier Dubanet ◽  
Arnaldo Ferreira Gomes Da Silva ◽  
Andreas Frick ◽  
Hajime Hirase ◽  
Anna Beyeler ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Neuronal Firing ◽  
Gabaergic Transmission ◽  
Chronic Epilepsy ◽  
Acute Seizures ◽  
Reversed Polarity ◽  
Excitatory Gaba ◽  
A Minor

AbstractSeveral studies suggest a contribution of reversed, excitatory GABA to epileptogenesis. But GABAergic transmission critically depends on the very dynamic combination of membrane potential, conductance and occurrence of other synaptic inputs. Taking this complexity into account implies measuring the postsynaptic responses to spontaneously occurring GABAergic events, in vivo, without interfering with neuronal [Cl-]i. Because of technical difficulties, this has not been achieved yet. We have overcome this challenge by combining in vivo extracellular detection of both optogenetically-evoked and spontaneously occurring unitary inhibitory postsynaptic field-potentials (fIPSPs), with the silicon probe recording of neuronal firing activity, with single cell resolution. We report that isolated acute seizures induced a global reversal of the polarity of CA3 hippocampal GABAergic transmission, shifting from inhibitory to excitatory for a duration of several tens of seconds before returning to normal polarity. Nevertheless we observed this reversed polarity only in the post-ictal period during which neurons (including GABAergic interneurons) were silent. Perisomatic inhibition was also affected during the course of epileptogenesis in the Kainate model of chronic epilepsy. One week after Kainate injection, the majority of pyramidal cells escaped inhibitory control by perisomatic GABAergic events. Besides, we did not observe a reversed polarity of fIPSPs, but fIPSPs provided time-locked excitation to a minor subset of CA3 pyramidal neurons. Beside methodological interests, our results suggest that subtle alterations in the regulation of [Cl-]i and perisomatic GABAergic transmission already operate in the hippocampal circuit during the latent period that precedes the establishment of chronic epilepsy.

scholarly journals A Multi-Scale Computational Model of the effects of TMS on Motor Cortex

2016 ◽  
Author(s):  
Hyeon Seo ◽  
Natalie Schaworonkow ◽  
Sung Chan Jun ◽  
Jochen Triesch
Keyword(s):  
Transcranial Magnetic Stimulation ◽  
Computational Model ◽  
Electric Fields ◽  
Action Potentials ◽  
Magnetic Stimulation ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Cell Types ◽  
Cortical Layer ◽  
Multi Scale

AbstractThe detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different cell types in motor cortex due to transcranial magnetic stimulation. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict detailed neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to predict activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons’ complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also predicts differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of corctial pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings.

scholarly journals Paradoxical hyperexcitability from NaV1.2 sodium channel loss in neocortical pyramidal cells

2021 ◽  
Author(s):  
Perry W.E. Spratt ◽  
Roy Ben-Shalom ◽  
Atehsa Sahagun ◽  
Caroline M. Keeshen ◽  
Stephan J. Sanders ◽  
...  
Keyword(s):  
Sodium Channel ◽  
High Frequency ◽  
Action Potentials ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
Autism Spectrum ◽  
Dynamic Clamp ◽  
Loss Of Function ◽  
Intrinsic Mechanism ◽  
Channel Loss

Loss-of-function variants in the gene SCN2A, which encodes the sodium channel NaV1.2, are strongly associated with autism spectrum disorder and intellectual disability. An estimated 20-30% of children with these variants are co-morbid for epilepsy, with altered neuronal activity originating in neocortex, a region where NaV1.2 channels are expressed predominantly in excitatory pyramidal cells. This is paradoxical, as sodium channel loss in excitatory cells would be expected to dampen neocortical activity rather than promote seizure. Here, we examined pyramidal neurons lacking NaV1.2 channels and found that they were intrinsically hyperexcitable, firing high-frequency bursts of action potentials (APs) despite decrements in AP size and speed. Compartmental modeling and dynamic clamp recordings revealed that NaV1.2 loss prevented potassium channels from properly repolarizing neurons between APs, increasing overall excitability by allowing neurons to reach threshold for subsequent APs more rapidly. This cell-intrinsic mechanism may therefore account for why SCN2A loss-of-function can paradoxically promote seizure.

Local and Propagated Dendritic Action Potentials Evoked by Glutamate Iontophoresis on Rat Neocortical Pyramidal Neurons

1997 ◽  
Vol 77 (5) ◽  
pp. 2466-2483 ◽  
Author(s):  
Peter C. Schwindt ◽  
Wayne E. Crill
Keyword(s):  
Action Potentials ◽  
Pyramidal Neurons ◽  
Apical Dendrite ◽  
Membrane Potentials ◽  
Current Injection ◽  
Resting Potential ◽  
Neural Input ◽  
Restricted Region ◽  
Low Threshold ◽  
Neocortical Pyramidal Neurons

Schwindt, Peter C. and Wayne E. Crill. Local and propagated dendritic action potentials evoked by glutamate iontophoresis on rat neocortical pyramidal neurons. J. Neurophysiol. 77: 2466–2483, 1997. Iontophoresis of glutamate at sites on the apical dendrite 278–555 μm from the somata of rat neocortical pyramidal neurons evoked low-threshold, small, slow spikes and/or large, fast spikes in 71% of recorded cells. The amplitude of the small, slow spikes recorded at the soma averaged 9.1 mV, and their apparent threshold was <10 mV positive to resting potential. Both their amplitude and their apparent threshold decreased as the iontophoretic site was moved farther from the soma. These spikes were not abolished by somatic hyperpolarization. When the somata of cells displaying these small spikes were voltage clamped at membrane potentials that prevented somatic or axonic firing, corresponding current spikes could be evoked all-or-none by dendritic depolarization, indicating that the small, slow spikes arose in the dendrite. Similar responses were not observed during somatic depolarization evoked by current pulses or glutamate iontophoresis. These small, slow spikes were abolished by blocking voltage-gated Ca2+ channels but not by blocking Na+ channels or N-methyl-d-aspartate receptors. We conclude that these Ca2+ spikes occurred in a spatially restricted region of the dendrite and were not actively propagated to the soma. In the presence of 10 mM tetraethylammonium chloride, the amplitudes of the iontophoretically evoked Ca2+ spikes were large, similar to those of the Ca2+ spikes evoked by somatic current injection, but their apparent thresholds were 63% lower. We conclude that dendritic K+ channels normally prevent the active propagation of Ca2+ spikes along the dendrite. In 36% of recorded cells dendritic glutamate iontophoresis evoked a Na+ spike with an apparent threshold 63% lower than those evoked by somatic current injection or somatic glutamate iontophoresis. Blockade of these low-threshold Na+ spikes by pharmacological or electrophysiological means often revealed underlying small dendritic Ca2+ spikes. When cells displaying the low-threshold Na+ spikes were voltage clamped at membrane potentials that prevented firing of the soma or axon, corresponding tetrodotoxin-sensitive current spikes could be evoked all-or-none by dendritic depolarization. We conclude that these low-threshold Na+ spikes were initiated in the dendrite, probably by local Ca2+ spikes, and subsequently propagated actively to the soma. Most cells displaying dendritic Na+ spikes fired multiple bursts of action potentials during tonic dendritic depolarization, whereas somatic depolarization of the same cells evoked only regular firing. We discuss the implications of dendritic Ca2+ and Na+ spikes for synaptic integration and neural input-output relations.

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