Author response: Sodium channels implement a molecular leaky integrator that detects action potentials and regulates neuronal firing

Voltage-gated sodium channels play a critical role in cellular excitability, amplifying small membrane depolarizations into action potentials. Interactions with auxiliary subunits and other factors modify the intrinsic kinetic mechanism to result in new molecular and cellular functionality. We show here that sodium channels can implement a molecular leaky integrator, where the input signal is the membrane potential and the output is the occupancy of a long-term inactivated state. Through this mechanism, sodium channels effectively measure the frequency of action potentials and convert it into Na+ current availability. In turn, the Na+ current can control neuronal firing frequency in a negative feedback loop. Consequently, neurons become less sensitive to changes in excitatory input and maintain a lower firing rate. We present these ideas in the context of rat serotonergic raphe neurons, which fire spontaneously at low frequency and provide critical neuromodulation to many autonomous and cognitive brain functions.

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Sodium Channels Implement a Molecular Leaky Integrator to Sense Spiking Frequency and Regulate Neuronal Firing

Biophysical Journal ◽

10.1016/j.bpj.2018.11.2101 ◽

2019 ◽

Vol 116 (3) ◽

pp. 388a

Author(s):

Marco A. Navarro ◽

Jenna Lin ◽

Autoosa Salari ◽

Mirela Milescu ◽

Lorin S. Milescu

Keyword(s):

Sodium Channels ◽

Neuronal Firing ◽

Leaky Integrator

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Author response for "Retinal horizontal cells of goldfish ( Carassius auratus ) display subtype‐specific differences in spontaneous action potentials in situ"

10.1002/cne.25054/v2/response1 ◽

2020 ◽

Author(s):

Michael W. Country ◽

Elly Dimya Htite ◽

Isaiah A. Samson ◽

Michael G. Jonz

Keyword(s):

Action Potentials ◽

Carassius Auratus ◽

Horizontal Cells ◽

Author Response ◽

Spontaneous Action ◽

Spontaneous Action Potentials

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Author response: Cannabidiol interactions with voltage-gated sodium channels

10.7554/elife.58593.sa2 ◽

2020 ◽

Author(s):

Lily Goodyer Sait ◽

Altin Sula ◽

Mohammad-Reza Ghovanloo ◽

David Hollingworth ◽

Peter C Ruben ◽

...

Keyword(s):

Sodium Channels ◽

Author Response ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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A sensory integration account for time perception

10.1101/2020.08.02.232801 ◽

2020 ◽

Author(s):

Alessandro Toso ◽

Arash Fassihi ◽

Luciano Paz ◽

Francesca Pulecchi ◽

Mathew E. Diamond

Keyword(s):

Time Perception ◽

Time Constant ◽

Sensory Integration ◽

Neuronal Firing ◽

Elapsed Time ◽

Leaky Integrator ◽

Long Time ◽

Integrator Model ◽

Short Time ◽

Sense Of Touch

ABSTRACTThe connection between stimulus perception and time perception remains unknown. The present study combines human and rat psychophysics with sensory cortical neuronal firing to construct a computational model for the percept of elapsed time embedded within sense of touch. When subjects judged the duration of a vibration applied to the fingertip (human) or whiskers (rat), increasing stimulus mean speed led to increasing perceived duration. Symmetrically, increasing vibration duration led to increasing perceived intensity. We modeled spike trains from vibrissal somatosensory cortex as input to dual leaky integrators – an intensity integrator with short time constant and a duration integrator with long time constant – generating neurometric functions that replicated the actual psychophysical functions of rats. Returning to human psychophysics, we then confirmed specific predictions of the dual leaky integrator model. This study offers a framework, based on sensory coding and subsequent accumulation of sensory drive, to account for how a feeling of the passage of time accompanies the tactile sensory experience.

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Contribution of Nav1.8 Sodium Channels to Action Potential Electrogenesis in DRG Neurons

Journal of Neurophysiology ◽

10.1152/jn.2001.86.2.629 ◽

2001 ◽

Vol 86 (2) ◽

pp. 629-640 ◽

Cited By ~ 339

Author(s):

Muthukrishnan Renganathan ◽

Theodore R. Cummins ◽

Stephen G. Waxman

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Action Potentials ◽

Input Resistance ◽

Resting Membrane Potential ◽

Drg Neurons ◽

Significant Difference ◽

Steady State Inactivation ◽

Current Threshold

C-type dorsal root ganglion (DRG) neurons can generate tetrodotoxin-resistant (TTX-R) sodium-dependent action potentials. However, multiple sodium channels are expressed in these neurons, and the molecular identity of the TTX-R sodium channels that contribute to action potential production in these neurons has not been established. In this study, we used current-clamp recordings to compare action potential electrogenesis in Nav1.8 (+/+) and (−/−) small DRG neurons maintained for 2–8 h in vitro to examine the role of sodium channel Nav1.8 (α-SNS) in action potential electrogenesis. Although there was no significant difference in resting membrane potential, input resistance, current threshold, or voltage threshold in Nav1.8 (+/+) and (−/−) DRG neurons, there were significant differences in action potential electrogenesis. Most Nav1.8 (+/+) neurons generate all-or-none action potentials, whereas most of Nav1.8 (−/−) neurons produce smaller graded responses. The peak of the response was significantly reduced in Nav1.8 (−/−) neurons [31.5 ± 2.2 (SE) mV] compared with Nav1.8 (+/+) neurons (55.0 ± 4.3 mV). The maximum rise slope was 84.7 ± 11.2 mV/ms in Nav1.8 (+/+) neurons, significantly faster than in Nav1.8 (−/−) neurons where it was 47.2 ± 1.3 mV/ms. Calculations based on the action potential overshoot in Nav1.8 (+/+) and (−/−) neurons, following blockade of Ca2+ currents, indicate that Nav1.8 contributes a substantial fraction (80–90%) of the inward membrane current that flows during the rising phase of the action potential. We found that fast TTX-sensitive Na+ channels can produce all-or-none action potentials in some Nav1.8 (−/−) neurons but, presumably as a result of steady-state inactivation of these channels, electrogenesis in Nav1.8 (−/−) neurons is more sensitive to membrane depolarization than in Nav1.8 (+/+) neurons, and, in the absence of Nav1.8, is attenuated with even modest depolarization. These observations indicate that Nav1.8 contributes substantially to action potential electrogenesis in C-type DRG neurons.

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Excitable Membrane Properties of Neurons

The Oxford Handbook of Neuronal Ion Channels ◽

10.1093/oxfordhb/9780190669164.013.20 ◽

2020 ◽

Author(s):

Leonard K. Kaczmarek

Keyword(s):

Action Potential ◽

Action Potentials ◽

Cell Biology ◽

Neuronal Firing ◽

Membrane Properties ◽

Potassium Ions ◽

Single Action ◽

Sodium Calcium ◽

Different Types ◽

Order Of Magnitude

The intrinsic electrical properties of neurons are extremely varied. For example, the width of action potentials in different neurons varies by more than an order of magnitude. In response to prolonged stimulation, some neurons generate repeated action potential hundreds of times a second, while others fire only a single action potential or adapt very rapidly. These differences result from the expression of different types of ion channels in the plasma membrane. The dominant channels that shape neuronal firing patterns are those that are selective for sodium, calcium, and potassium ions. This chapter provides a brief overview of the biophysical properties of each of these classes of channel, their role in shaping the electrical personality of a neuron, and how interactions of these channels with cytoplasmic factors shape the overall cell biology of a neuron.

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