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Biophysical basis for three distinct dynamical mechanisms of action potential initiation.

Prescott SA, De Koninck Y, Sejnowski TJ - PLoS Comput. Biol. (2008)

Bottom Line: Hodgkin identified three classes of neurons with qualitatively different analog-to-digital transduction properties.From this, we conclude that the spike-initiating dynamics associated with each of Hodgkin's classes represent different outcomes in a nonlinear competition between oppositely directed, kinetically mismatched currents.Through detailed analysis of the spike-initiating process, we have explained a fundamental link between biophysical properties and qualitative differences in how neurons encode sensory input.

View Article: PubMed Central - PubMed

Affiliation: Computational Neurobiology Laboratory, Salk Institute, La Jolla, California, United States of America. prescott@neurobio.pitt.edu

ABSTRACT
Transduction of graded synaptic input into trains of all-or-none action potentials (spikes) is a crucial step in neural coding. Hodgkin identified three classes of neurons with qualitatively different analog-to-digital transduction properties. Despite widespread use of this classification scheme, a generalizable explanation of its biophysical basis has not been described. We recorded from spinal sensory neurons representing each class and reproduced their transduction properties in a minimal model. With phase plane and bifurcation analysis, each class of excitability was shown to derive from distinct spike initiating dynamics. Excitability could be converted between all three classes by varying single parameters; moreover, several parameters, when varied one at a time, had functionally equivalent effects on excitability. From this, we conclude that the spike-initiating dynamics associated with each of Hodgkin's classes represent different outcomes in a nonlinear competition between oppositely directed, kinetically mismatched currents. Class 1 excitability occurs through a saddle node on invariant circle bifurcation when net current at perithreshold potentials is inward (depolarizing) at steady state. Class 2 excitability occurs through a Hopf bifurcation when, despite net current being outward (hyperpolarizing) at steady state, spike initiation occurs because inward current activates faster than outward current. Class 3 excitability occurs through a quasi-separatrix crossing when fast-activating inward current overpowers slow-activating outward current during a stimulus transient, although slow-activating outward current dominates during constant stimulation. Experiments confirmed that different classes of spinal lamina I neurons express the subthreshold currents predicted by our simulations and, further, that those currents are necessary for the excitability in each cell class. Thus, our results demonstrate that all three classes of excitability arise from a continuum in the direction and magnitude of subthreshold currents. Through detailed analysis of the spike-initiating process, we have explained a fundamental link between biophysical properties and qualitative differences in how neurons encode sensory input.

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Necessity of oppositely directed subthreshold currents to explainexcitability in spinal lamina I neurons.(A) Blocking a subthreshold Ca2+ current withNi2+ converted tonic-spiking neurons tophasic-spiking (right). Blocking a subthreshold K+current with 4-AP converted single-spiking neurons to phasic-spiking(left). Compare with naturally occurring phasic-spiking pattern(center). (B) Application of Ni2+ and 4-AP convertedclass 1 and 3 neurons, respectively, to class 2 neurons according to thef–I curves. Firing rate was determinedfrom the reciprocal of first interspike interval. According to thesedata, a subthreshold inward current is necessary for class 1excitability, a subthreshold outward current is necessary for class 3excitability, and class 2 excitability occurs when neither current ispresent.
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pcbi-1000198-g006: Necessity of oppositely directed subthreshold currents to explainexcitability in spinal lamina I neurons.(A) Blocking a subthreshold Ca2+ current withNi2+ converted tonic-spiking neurons tophasic-spiking (right). Blocking a subthreshold K+current with 4-AP converted single-spiking neurons to phasic-spiking(left). Compare with naturally occurring phasic-spiking pattern(center). (B) Application of Ni2+ and 4-AP convertedclass 1 and 3 neurons, respectively, to class 2 neurons according to thef–I curves. Firing rate was determinedfrom the reciprocal of first interspike interval. According to thesedata, a subthreshold inward current is necessary for class 1excitability, a subthreshold outward current is necessary for class 3excitability, and class 2 excitability occurs when neither current ispresent.

Mentions: Thus, lamina I neurons express the sort of currents predicted by our model, butthat result is purely correlative, i.e., based on comparison of simulated andexperimental I–V curves. Are the identified currentsnecessary and sufficient to explain differences in the excitability of lamina Ineurons? One prediction is that blocking the subthreshold inward current inclass 1 neurons, or the subthreshold outward current in class 3 neurons, shouldconvert those neurons to class 2 excitability. To test this, wepharmacologically blocked the low-threshold Ca2+ orK+ current in class 1 and 3 neurons, respectively. Aspredicted, spiking was converted to a phasic pattern (Figure 6A) and f–Icurves became discontinuous (Figure6B) in both cases, consistent with conversion to class 2excitability. This demonstrates the necessity, in spinal lamina I neurons atleast, of subthreshold inward and outward currents for producing class 1 and 3excitability, respectively.


Biophysical basis for three distinct dynamical mechanisms of action potential initiation.

Prescott SA, De Koninck Y, Sejnowski TJ - PLoS Comput. Biol. (2008)

Necessity of oppositely directed subthreshold currents to explainexcitability in spinal lamina I neurons.(A) Blocking a subthreshold Ca2+ current withNi2+ converted tonic-spiking neurons tophasic-spiking (right). Blocking a subthreshold K+current with 4-AP converted single-spiking neurons to phasic-spiking(left). Compare with naturally occurring phasic-spiking pattern(center). (B) Application of Ni2+ and 4-AP convertedclass 1 and 3 neurons, respectively, to class 2 neurons according to thef–I curves. Firing rate was determinedfrom the reciprocal of first interspike interval. According to thesedata, a subthreshold inward current is necessary for class 1excitability, a subthreshold outward current is necessary for class 3excitability, and class 2 excitability occurs when neither current ispresent.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551735&req=5

pcbi-1000198-g006: Necessity of oppositely directed subthreshold currents to explainexcitability in spinal lamina I neurons.(A) Blocking a subthreshold Ca2+ current withNi2+ converted tonic-spiking neurons tophasic-spiking (right). Blocking a subthreshold K+current with 4-AP converted single-spiking neurons to phasic-spiking(left). Compare with naturally occurring phasic-spiking pattern(center). (B) Application of Ni2+ and 4-AP convertedclass 1 and 3 neurons, respectively, to class 2 neurons according to thef–I curves. Firing rate was determinedfrom the reciprocal of first interspike interval. According to thesedata, a subthreshold inward current is necessary for class 1excitability, a subthreshold outward current is necessary for class 3excitability, and class 2 excitability occurs when neither current ispresent.
Mentions: Thus, lamina I neurons express the sort of currents predicted by our model, butthat result is purely correlative, i.e., based on comparison of simulated andexperimental I–V curves. Are the identified currentsnecessary and sufficient to explain differences in the excitability of lamina Ineurons? One prediction is that blocking the subthreshold inward current inclass 1 neurons, or the subthreshold outward current in class 3 neurons, shouldconvert those neurons to class 2 excitability. To test this, wepharmacologically blocked the low-threshold Ca2+ orK+ current in class 1 and 3 neurons, respectively. Aspredicted, spiking was converted to a phasic pattern (Figure 6A) and f–Icurves became discontinuous (Figure6B) in both cases, consistent with conversion to class 2excitability. This demonstrates the necessity, in spinal lamina I neurons atleast, of subthreshold inward and outward currents for producing class 1 and 3excitability, respectively.

Bottom Line: Hodgkin identified three classes of neurons with qualitatively different analog-to-digital transduction properties.From this, we conclude that the spike-initiating dynamics associated with each of Hodgkin's classes represent different outcomes in a nonlinear competition between oppositely directed, kinetically mismatched currents.Through detailed analysis of the spike-initiating process, we have explained a fundamental link between biophysical properties and qualitative differences in how neurons encode sensory input.

View Article: PubMed Central - PubMed

Affiliation: Computational Neurobiology Laboratory, Salk Institute, La Jolla, California, United States of America. prescott@neurobio.pitt.edu

ABSTRACT
Transduction of graded synaptic input into trains of all-or-none action potentials (spikes) is a crucial step in neural coding. Hodgkin identified three classes of neurons with qualitatively different analog-to-digital transduction properties. Despite widespread use of this classification scheme, a generalizable explanation of its biophysical basis has not been described. We recorded from spinal sensory neurons representing each class and reproduced their transduction properties in a minimal model. With phase plane and bifurcation analysis, each class of excitability was shown to derive from distinct spike initiating dynamics. Excitability could be converted between all three classes by varying single parameters; moreover, several parameters, when varied one at a time, had functionally equivalent effects on excitability. From this, we conclude that the spike-initiating dynamics associated with each of Hodgkin's classes represent different outcomes in a nonlinear competition between oppositely directed, kinetically mismatched currents. Class 1 excitability occurs through a saddle node on invariant circle bifurcation when net current at perithreshold potentials is inward (depolarizing) at steady state. Class 2 excitability occurs through a Hopf bifurcation when, despite net current being outward (hyperpolarizing) at steady state, spike initiation occurs because inward current activates faster than outward current. Class 3 excitability occurs through a quasi-separatrix crossing when fast-activating inward current overpowers slow-activating outward current during a stimulus transient, although slow-activating outward current dominates during constant stimulation. Experiments confirmed that different classes of spinal lamina I neurons express the subthreshold currents predicted by our simulations and, further, that those currents are necessary for the excitability in each cell class. Thus, our results demonstrate that all three classes of excitability arise from a continuum in the direction and magnitude of subthreshold currents. Through detailed analysis of the spike-initiating process, we have explained a fundamental link between biophysical properties and qualitative differences in how neurons encode sensory input.

Show MeSH
Related in: MedlinePlus