On the mechanisms underlying the depolarization block in the spiking dynamics of CA1 pyramidal neurons

Bianchi, Daniela; Marasco, Addolorata; Limongiello, Alessandro; Marchetti, Cristina; Marie, Hélène; Tirozzi, B.; Migliore, Michele

doi:10.1007/s10827-012-0383-y

Cited by 128 publications

(156 citation statements)

References 37 publications

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“…The difference between the responses of the soma and dendrites was most likely due to the much higher density of HCN channels in dendrites than in soma [27,37] . Moreover, we found that modifying the Na + channel or kdr channel alone facilitated depolarization block, consistent with previous studies [31] . In contrast, modifying the HCN channel alone increased the depolarization block threshold, which is likely attributable to the decrease in the input resistance.…”

Section: Discussionsupporting

confidence: 93%

“…Depolarization block is proposed to be associated with the initiation and spread of focal epileptic seizures that generates a paroxysmal depolarizing effect in the involved neurons, which may cause the inactivation of Na + channels [31][32][33]52] . In our study, the effects of SKF83959 on Na + channel density and on the Na + channel inactivation curve facilitated depolarization block in hippocampal pyramidal neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Modeling studies have suggested that depolarization block could happen in vivo, and it has been suggested that depolarization block could play an important role in some pathological conditions, such as epilepsy [31] . Because both Na + and kdr channels affect depolarization block, we examined the effects of SKF83959 on the amplitude of the minimal current required to induce depolarization block by current injection at the soma, while compensating the membrane potential to the control level.…”

Section: Skf83959 Facilitates Depolarization Block In Hippocampal Pyrmentioning

confidence: 99%

“…Some types of neurons, such as pyramidal neurons in the hippocampus and dopaminergic neurons in the midbrain, cease firing when the stimulus is too strong; this phenomenon is known as depolarization block [30,31] . Depolarization block is regarded to have pathological relevance for some brain disorders, including epilepsy and schizophrenia [32][33][34] .…”

Section: Introductionmentioning

confidence: 99%

“…Depolarization block is regarded to have pathological relevance for some brain disorders, including epilepsy and schizophrenia [32][33][34] . Among all the mechanisms known to cause depolarization block, the inactivation of voltage-dependent Na + channels is believed to play a key role [31,35,36] . SKF83959 can decrease the amplitude of Na + currents [17] ; however, whether the drug has an effect on the depolarization block of pyramidal neurons in the hippocampus remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

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Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

et al. 2014

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Aim: 3-Methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF83959) have been shown to affect several types of voltage-dependent channels in hippocampal pyramidal neurons. The aim of this study was to determine how modulation of a individual type of the channels by SKF83959 contributes to the overall excitability of CA1 pyramidal neurons during either direct current injections or synaptic activation. Methods: Rat hippocampal slices were prepared. The kinetics of voltage-dependent Na + channels and neuronal excitability and depolarization block in CA1 pyramidal neurons were examined using whole-cell recording. A realistic mathematical model of hippocampal CA1 pyramidal neuron was used to simulate the effects of SKF83959 on neuronal excitability. Results: SKF83959 (50 μmol/L) shifted the inactivation curve of Na + current by 10.3 mV but had no effect on the activation curve in CA1 pyramidal neurons. The effects of SKF83959 on passive membrane properties, including a decreased input resistance and depolarized resting potential, predicted by our simulations were in agreement with the experimental data. The simulations showed that decreased excitability of the soma by SKF83959 (examined with current injection at the soma) was only observed when the membrane potential was compensated to the control levels, whereas the decreased dendritic excitability (examined with current injection at the dendrite) was found even without membrane potential compensation, which led to a decreased number of action potentials initiated at the soma. Moreover, SKF83959 significantly facilitated depolarization block in CA1 pyramidal neurons. SKF83959 decreased EPSP temporal summation and, of physiologically greater relevance, the synaptic-driven firing frequency. Conclusion: SKF83959 decreased the excitability of CA1 pyramidal neurons even though the drug caused the membrane potential depolarization. The results may reveal a partial mechanism for the drug's anti-Parkinsonian effects and may also suggest that SKF83959 has a potential antiepileptic effect.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Skf83959 Facilitates Depolarization Block In Hippocampal Pyrmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

et al. 2014

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SCN1A gain of function in early infantile encephalopathy

Berecki

Bryson

Terhag

et al. 2019

Annals of Neurology

113

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Objective: To elucidate the biophysical basis underlying the distinct and severe clinical presentation in patients with the recurrent missense SCN1A variant, p.Thr226Met. Patients with this variant show a well-defined genotypephenotype correlation and present with developmental and early infantile epileptic encephalopathy that is far more severe than typical SCN1A Dravet syndrome. Methods: Whole cell patch clamp and dynamic action potential clamp were used to study T226M Na v 1.1 channels expressed in mammalian cells. Computational modeling was used to explore the neuronal scale mechanisms that account for altered action potential firing. Results: T226M channels exhibited hyperpolarizing shifts of the activation and inactivation curves and enhanced fast inactivation. Dynamic action potential clamp hybrid simulation showed that model neurons containing T226M conductance displayed a left shift in rheobase relative to control. At current stimulation levels that produced repetitive action potential firing in control model neurons, depolarization block and cessation of action potential firing occurred in T226M model neurons. Fully computationally simulated neuron models recapitulated the findings from dynamic action potential clamp and showed that heterozygous T226M models were also more susceptible to depolarization block. Interpretation: From a biophysical perspective, the T226M mutation produces gain of function. Somewhat paradoxically, our data suggest that this gain of function would cause interneurons to more readily develop depolarization block. This "functional dominant negative" interaction would produce a more profound disinhibition than seen with haploinsufficiency that is typical of Dravet syndrome and could readily explain the more severe phenotype of patients with T226M mutation.

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Picosecond Pulse Electrical Field Suppressing Spike Firing in Hippocampal CA1 in Rat In Vivo

Wang

Zhang³

et al. 2020

Bioelectromagnetics

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Picosecond pulse electrical fields (psPEFs), due to their high temporal-resolution accuracy and localization, were viewed as a potential targeted and noninvasive method for neuromodulation. However, few studies have reported psPEFs regulating neuronal activity in vivo. In this paper, a preliminary study on psPEFs regulating action potentials in hippocampus CA1 of rats in vivo was carried out. By analyzing the neuronal spike firing rate in hippocampus CA1 pre-and post-psPEF stimulation, effects of frequency, duration, and dosimetry of psPEFs were studied. The psPEF used in this study had a pulse width of 500 ps and a field strength of 1 kV/mm, established by 1 kV picosecond voltage pulses. Results showed that the psPEF suppressed spike firing in hippocampal CA1 neurons. The suppression effect was found to be significant except for 10 s, 10 Hz. For shortduration stimulation (10 s), the inhibition rate of spike firing increased with frequency. At longer stimulation durations (1 and 2 min), the inhibition rate increased and decreased alternately as the frequency increased. Despite this, the inhibition rate at high frequencies (5 and 10 kHz) was significantly larger than that at 10 and 100 Hz. A cumulative effect of psPEF on spike firing inhibition was found at low frequencies (10 and 100 Hz), which was saturated when frequency reached 500 Hz or higher. This paper conducts a study on psPEF regulating spike firing in hippocampal CA1 in vivo for the first time and guides subsequent study on psPEF achieving noninvasive neuromodulation. Bioelectromagnetics. 2020;41:617-629.

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On the mechanisms underlying the depolarization block in the spiking dynamics of CA1 pyramidal neurons

Cited by 128 publications

References 37 publications

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

Effects of SKF83959 on the excitability of hippocampal CA1 pyramidal neurons: a modeling study

SCN1A gain of function in early infantile encephalopathy

Picosecond Pulse Electrical Field Suppressing Spike Firing in Hippocampal CA1 in Rat In Vivo

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