Sodium Channels Implement a Molecular Leaky Integrator to Sense Spiking Frequency and Regulate 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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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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Control of neuronal excitability by phosphorylation and dephosphorylation of sodium channels

Biochemical Society Transactions ◽

10.1042/bst0341299 ◽

2006 ◽

Vol 34 (6) ◽

pp. 1299-1302 ◽

Cited By ~ 22

Author(s):

T. Scheuer ◽

W.A. Catterall

Keyword(s):

Protein Kinases ◽

Sodium Channels ◽

Neuronal Excitability ◽

Sodium Current ◽

Molecular Complexes ◽

Neuronal Firing ◽

Signal Integration ◽

Excitable Cells ◽

Signalling Molecules ◽

Voltage Gated Sodium Channels

Currents through voltage-gated sodium channels drive action potential depolarization in neurons and other excitable cells. Smaller currents through these channels are key components of currents that control neuronal firing and signal integration. Changes in sodium current have profound effects on neuronal firing. Sodium channels are controlled by neuromodulators acting through phosphorylation of the channel by serine/threonine and tyrosine protein kinases. That phosphorylation requires specific molecular interaction of kinases and phosphatases with the channel molecule to form localized signalling complexes. Such localization is required for effective neurotransmitter-mediated regulation of sodium channels by protein kinase A. Analogous molecular complexes between sodium channels, kinases and other signalling molecules are expected to be necessary for specific and localized transmitter-mediated modulation of sodium channels by other protein kinases.

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The Appearance Order of Varying Intervals Introduces Extra Modulation Effects on Neuronal Firing Through Non-linear Dynamics of Sodium Channels During High-Frequency Stimulations

Frontiers in Neuroscience ◽

10.3389/fnins.2020.00397 ◽

2020 ◽

Vol 14 ◽

Cited By ~ 1

Author(s):

Lvpiao Zheng ◽

Zhouyan Feng ◽

Hanhan Hu ◽

Zhaoxiang Wang ◽

Yue Yuan ◽

...

Keyword(s):

Sodium Channels ◽

High Frequency ◽

Neuronal Firing ◽

Linear Dynamics ◽

Non Linear

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Consequences of Astroglial Modulation of Extracellular Calcium Concentration on Neuronal Firing Involving Sodium Channels

Biophysical Journal ◽

10.1016/j.bpj.2019.11.1893 ◽

2020 ◽

Vol 118 (3) ◽

pp. 340a

Author(s):

Arlette Kolta

Keyword(s):

Sodium Channels ◽

Calcium Concentration ◽

Extracellular Calcium ◽

Neuronal Firing ◽

Extracellular Calcium Concentration

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A sensory integration account for time perception

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008668 ◽

2021 ◽

Vol 17 (1) ◽

pp. e1008668

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

The 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 intensity led to increasing perceived duration. Symmetrically, increasing vibration duration led to increasing perceived intensity. We modeled real spike trains recorded 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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Distinctive Properties and Powerful Neuromodulation of Nav1.6 Sodium Channels Regulates Neuronal Excitability

Cells ◽

10.3390/cells10071595 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1595

Author(s):

Agnes Zybura ◽

Andy Hudmon ◽

Theodore R. Cummins

Keyword(s):

Sodium Channels ◽

Protein Interactions ◽

Neuronal Excitability ◽

Neuronal Firing ◽

Protein Protein Interactions ◽

Membrane Excitability ◽

Voltage Gated Sodium Channels ◽

Complex Modes ◽

Firing Properties ◽

And Function

Voltage-gated sodium channels (Navs) are critical determinants of cellular excitability. These ion channels exist as large heteromultimeric structures and their activity is tightly controlled. In neurons, the isoform Nav1.6 is highly enriched at the axon initial segment and nodes, making it critical for the initiation and propagation of neuronal impulses. Changes in Nav1.6 expression and function profoundly impact the input-output properties of neurons in normal and pathological conditions. While mutations in Nav1.6 may cause channel dysfunction, aberrant changes may also be the result of complex modes of regulation, including various protein-protein interactions and post-translational modifications, which can alter membrane excitability and neuronal firing properties. Despite decades of research, the complexities of Nav1.6 modulation in health and disease are still being determined. While some modulatory mechanisms have similar effects on other Nav isoforms, others are isoform-specific. Additionally, considerable progress has been made toward understanding how individual protein interactions and/or modifications affect Nav1.6 function. However, there is still more to be learned about how these different modes of modulation interact. Here, we examine the role of Nav1.6 in neuronal function and provide a thorough review of this channel’s complex regulatory mechanisms and how they may contribute to neuromodulation.

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Measurement of spontaneous neuronal membrane activity by time lapse confocal microscopy

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100141238 ◽

1995 ◽

Vol 53 ◽

pp. 972-973

Author(s):

R H. Selinfreund ◽

A. H. Cornell-Bell

Keyword(s):

Membrane Potential ◽

Confocal Microscopy ◽

Patch Clamp ◽

Electrical Activity ◽

Time Lapse ◽

Neuronal Firing ◽

Neuronal Membrane ◽

Pituitary Cells ◽

Patch Clamp Recording ◽

Spontaneous Electrical Activity

Cellular electrophysiological properties are normally monitored by standard patch clamp techniques . The combination of membrane potential dyes with time-lapse laser confocal microscopy provides a more direct, least destructive rapid method for monitoring changes in neuronal electrical activity. Using membrane potential dyes we found that spontaneous action potential firing can be detected using time-lapse confocal microscopy. Initially, patch clamp recording techniques were used to verify spontaneous electrical activity in GH4\C1 pituitary cells. It was found that serum depleted cells had reduced spontaneous electrical activity. Brief exposure to the serum derived growth factor, IGF-1, reconstituted electrical activity. We have examined the possibility of developing a rapid fluorescent assay to measure neuronal activity using membrane potential dyes. This neuronal regeneration assay has been adapted to run on a confocal microscope. Quantitative fluorescence is then used to measure a compounds ability to regenerate neuronal firing.The membrane potential dye di-8-ANEPPS was selected for these experiments. Di-8- ANEPPS is internalized slowly, has a high signal to noise ratio (40:1), has a linear fluorescent response to change in voltage.

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