title: Using multi-compartment ensemble modeling as an investigative tool of spatially distributed biophysical balances: application to hippocampal oriens-lacunosum/moleculare (O-LM) cells.
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.
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vladislav
authors.initials: V
authors.lastname: Sekulić
authors.affiliation: NIH COBRE Center for Structural and Functional Neuroscience, University of Montana, Missoula, Montana, United States of America; Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana, United States of America.
authors.forename: J Josh
authors.initials: JJ
authors.lastname: Lawrence
authors.affiliation: Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Medicine (Neurology), University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Frances K
authors.initials: FK
authors.lastname: Skinner
mesh_terms: D000818:Animals; D001703:Biophysics / Q000379:methods; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000502:physiology; D016000:Cluster Analysis; D003198:Computer Simulation; D016208:Databases, Factual; D003712:Dendrites / Q000502:physiology; D004594:Electrophysiology / Q000379:methods; D006624:Hippocampus / Q000166:cytology*; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000502:physiology; D007395:Interneurons / Q000502:physiology*; D008815:Mice, Inbred Strains; D008954:Models, Biological
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels