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Using multi-compartment ensemble modeling as an investigative tool of spatially distributed biophysical balances: application to hippocampal oriens-lacunosum/moleculare (O-LM) cells.

Sekulić V, Lawrence JJ, Skinner FK - PLoS ONE (2014)

Bottom Line: Models were quantified and ranked based on minimal error compared to a dataset of O-LM cell electrophysiological properties.Co-regulatory balances between conductances were revealed, two of which were dependent on the presence of dendritic Ih.These findings inform future experiments that differentiate between somatic and dendritic Ih, thereby continuing a cycle between model and experiment.

View Article: PubMed Central - PubMed

Affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
Multi-compartmental models of neurons provide insight into the complex, integrative properties of dendrites. Because it is not feasible to experimentally determine the exact density and kinetics of each channel type in every neuronal compartment, an essential goal in developing models is to help characterize these properties. To address biological variability inherent in a given neuronal type, there has been a shift away from using hand-tuned models towards using ensembles or populations of models. In collectively capturing a neuron's output, ensemble modeling approaches uncover important conductance balances that control neuronal dynamics. However, conductances are never entirely known for a given neuron class in terms of its types, densities, kinetics and distributions. Thus, any multi-compartment model will always be incomplete. In this work, our main goal is to use ensemble modeling as an investigative tool of a neuron's biophysical balances, where the cycling between experiment and model is a design criterion from the start. We consider oriens-lacunosum/moleculare (O-LM) interneurons, a prominent interneuron subtype that plays an essential gating role of information flow in hippocampus. O-LM cells express the hyperpolarization-activated current (Ih). Although dendritic Ih could have a major influence on the integrative properties of O-LM cells, the compartmental distribution of Ih on O-LM dendrites is not known. Using a high-performance computing cluster, we generated a database of models that included those with or without dendritic Ih. A range of conductance values for nine different conductance types were used, and different morphologies explored. Models were quantified and ranked based on minimal error compared to a dataset of O-LM cell electrophysiological properties. Co-regulatory balances between conductances were revealed, two of which were dependent on the presence of dendritic Ih. These findings inform future experiments that differentiate between somatic and dendritic Ih, thereby continuing a cycle between model and experiment.

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Virtual protocol on models indicates how dendritic Ih may be detected experimentally.Highly-ranked models were subjected to a mixed voltage/current clamp virtual experimental protocol as described in the main text. Somatic and dendritic traces for a highly-ranked model with Ih in soma and dendrites (A) and Ih in soma only (B). The maximum conductance density for gh was 0.5 pS/µm2 for the model with Ih in soma and dendrites (A) and 0.3 pS/µm2 for the model with Ih in soma only (B). Both models used morphology 1. Somatic traces are shown in black, and dendritic voltage traces, measured along various points on the same dendritic branch, are shown at distances for both models as per the figure legend (all numbers in µm).
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pone-0106567-g008: Virtual protocol on models indicates how dendritic Ih may be detected experimentally.Highly-ranked models were subjected to a mixed voltage/current clamp virtual experimental protocol as described in the main text. Somatic and dendritic traces for a highly-ranked model with Ih in soma and dendrites (A) and Ih in soma only (B). The maximum conductance density for gh was 0.5 pS/µm2 for the model with Ih in soma and dendrites (A) and 0.3 pS/µm2 for the model with Ih in soma only (B). Both models used morphology 1. Somatic traces are shown in black, and dendritic voltage traces, measured along various points on the same dendritic branch, are shown at distances for both models as per the figure legend (all numbers in µm).

Mentions: We next considered how one might assess whether dendritic Ih is present in O-LM cells, noting that we already know that Ih is present in O-LM cells [19], so it is not simply a matter of applying pharmacological blockers. We developed a virtual experimental protocol and applied it using highly-ranked models of both morphologies, Ih distributions, and high vs. low Ih conductance densities, that is, a total of eight different highly-ranked models. The protocol consisted of a mixed voltage clamp/current clamp virtual experimental protocol as follows: somata were held at a resting membrane potential of −74 mV using a voltage clamp while, simultaneously, a current clamp provided –5 nA (for morphology 1) or –2 nA (for morphology 2) hyperpolarizing tonic pulse in a proximal dendrite of the models 30 µm away from the soma. A distance of 30 µm was chosen as it was deemed to be far enough to consider for dendritic Ih presence, but not too far to be too difficult, given the extreme challenges in performing dendritic recordings on inhibitory cells. Applying this protocol to the eight highly-ranked models in our ensemble of different characteristics allowed us to evaluate the presence of dendritic Ih. The somatic voltage responses did not demonstrate a sag both in cases of models with somatodendritic Ih (Fig. 8A, black trace) and somatic Ih only distributions (Fig. 8B, black trace). Only models with high Ih in dendrites showed any demonstrable sag (Fig. 8A, colored traces, with maximum gh of 0.5 pS/µm2), except in the case when the dendritic Ih conductance was low (traces not shown). Furthermore, voltage measurements further away from the soma along the same dendritic branch showed less hyperpolarized steady-state values with more pronounced sag (Fig. 8A). On the other hand, lack of dendritic Ih consistently resulted in no sag response even with high Ih conductance (Fig. 8B, colored traces, with maximum gh of 0.3 pS/µm2). Crucially, no models with somatic Ih only exhibited any sag response with the protocol, indicating that any somatic sag current effects do not propagate to dendrites. Thus, we conclude that for a sag to be measured in an O-LM cell using the mixed VC/IC setup as outlined above, Ih must be present in the dendrites at high enough densities. We note that these “high densities” are consistently lower than those measured in pyramidal cells [28].


Using multi-compartment ensemble modeling as an investigative tool of spatially distributed biophysical balances: application to hippocampal oriens-lacunosum/moleculare (O-LM) cells.

Sekulić V, Lawrence JJ, Skinner FK - PLoS ONE (2014)

Virtual protocol on models indicates how dendritic Ih may be detected experimentally.Highly-ranked models were subjected to a mixed voltage/current clamp virtual experimental protocol as described in the main text. Somatic and dendritic traces for a highly-ranked model with Ih in soma and dendrites (A) and Ih in soma only (B). The maximum conductance density for gh was 0.5 pS/µm2 for the model with Ih in soma and dendrites (A) and 0.3 pS/µm2 for the model with Ih in soma only (B). Both models used morphology 1. Somatic traces are shown in black, and dendritic voltage traces, measured along various points on the same dendritic branch, are shown at distances for both models as per the figure legend (all numbers in µm).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215854&req=5

pone-0106567-g008: Virtual protocol on models indicates how dendritic Ih may be detected experimentally.Highly-ranked models were subjected to a mixed voltage/current clamp virtual experimental protocol as described in the main text. Somatic and dendritic traces for a highly-ranked model with Ih in soma and dendrites (A) and Ih in soma only (B). The maximum conductance density for gh was 0.5 pS/µm2 for the model with Ih in soma and dendrites (A) and 0.3 pS/µm2 for the model with Ih in soma only (B). Both models used morphology 1. Somatic traces are shown in black, and dendritic voltage traces, measured along various points on the same dendritic branch, are shown at distances for both models as per the figure legend (all numbers in µm).
Mentions: We next considered how one might assess whether dendritic Ih is present in O-LM cells, noting that we already know that Ih is present in O-LM cells [19], so it is not simply a matter of applying pharmacological blockers. We developed a virtual experimental protocol and applied it using highly-ranked models of both morphologies, Ih distributions, and high vs. low Ih conductance densities, that is, a total of eight different highly-ranked models. The protocol consisted of a mixed voltage clamp/current clamp virtual experimental protocol as follows: somata were held at a resting membrane potential of −74 mV using a voltage clamp while, simultaneously, a current clamp provided –5 nA (for morphology 1) or –2 nA (for morphology 2) hyperpolarizing tonic pulse in a proximal dendrite of the models 30 µm away from the soma. A distance of 30 µm was chosen as it was deemed to be far enough to consider for dendritic Ih presence, but not too far to be too difficult, given the extreme challenges in performing dendritic recordings on inhibitory cells. Applying this protocol to the eight highly-ranked models in our ensemble of different characteristics allowed us to evaluate the presence of dendritic Ih. The somatic voltage responses did not demonstrate a sag both in cases of models with somatodendritic Ih (Fig. 8A, black trace) and somatic Ih only distributions (Fig. 8B, black trace). Only models with high Ih in dendrites showed any demonstrable sag (Fig. 8A, colored traces, with maximum gh of 0.5 pS/µm2), except in the case when the dendritic Ih conductance was low (traces not shown). Furthermore, voltage measurements further away from the soma along the same dendritic branch showed less hyperpolarized steady-state values with more pronounced sag (Fig. 8A). On the other hand, lack of dendritic Ih consistently resulted in no sag response even with high Ih conductance (Fig. 8B, colored traces, with maximum gh of 0.3 pS/µm2). Crucially, no models with somatic Ih only exhibited any sag response with the protocol, indicating that any somatic sag current effects do not propagate to dendrites. Thus, we conclude that for a sag to be measured in an O-LM cell using the mixed VC/IC setup as outlined above, Ih must be present in the dendrites at high enough densities. We note that these “high densities” are consistently lower than those measured in pyramidal cells [28].

Bottom Line: Models were quantified and ranked based on minimal error compared to a dataset of O-LM cell electrophysiological properties.Co-regulatory balances between conductances were revealed, two of which were dependent on the presence of dendritic Ih.These findings inform future experiments that differentiate between somatic and dendritic Ih, thereby continuing a cycle between model and experiment.

View Article: PubMed Central - PubMed

Affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
Multi-compartmental models of neurons provide insight into the complex, integrative properties of dendrites. Because it is not feasible to experimentally determine the exact density and kinetics of each channel type in every neuronal compartment, an essential goal in developing models is to help characterize these properties. To address biological variability inherent in a given neuronal type, there has been a shift away from using hand-tuned models towards using ensembles or populations of models. In collectively capturing a neuron's output, ensemble modeling approaches uncover important conductance balances that control neuronal dynamics. However, conductances are never entirely known for a given neuron class in terms of its types, densities, kinetics and distributions. Thus, any multi-compartment model will always be incomplete. In this work, our main goal is to use ensemble modeling as an investigative tool of a neuron's biophysical balances, where the cycling between experiment and model is a design criterion from the start. We consider oriens-lacunosum/moleculare (O-LM) interneurons, a prominent interneuron subtype that plays an essential gating role of information flow in hippocampus. O-LM cells express the hyperpolarization-activated current (Ih). Although dendritic Ih could have a major influence on the integrative properties of O-LM cells, the compartmental distribution of Ih on O-LM dendrites is not known. Using a high-performance computing cluster, we generated a database of models that included those with or without dendritic Ih. A range of conductance values for nine different conductance types were used, and different morphologies explored. Models were quantified and ranked based on minimal error compared to a dataset of O-LM cell electrophysiological properties. Co-regulatory balances between conductances were revealed, two of which were dependent on the presence of dendritic Ih. These findings inform future experiments that differentiate between somatic and dendritic Ih, thereby continuing a cycle between model and experiment.

Show MeSH