Computationally going where experiments cannot: a dynamical assessment of dendritic ion channel currents during in vivo-like states

Abstract

Background: Despite technological advances, how specific cell types are involved in brain function remains shrouded in mystery. Further, little is known about the contribution of different ion channel currents to cell excitability across different neuronal subtypes and their dendritic compartments in vivo. The picture that we do have is largely based on somatic recordings performed in vitro. Uncovering dendritic ion channel current contributions in neuron subtypes that represent a minority of the neuronal population is not currently a feasible task using purely experimental means. Methods: We employ two morphologically-detailed multi-compartment models of a specific type of inhibitory interneuron, the oriens lacunosum moleculare (OLM) cell. The OLM cell is a well-studied cell type in CA1 hippocampus that is important in gating sensory and contextual information. We create in vivo-like states for these cellular models by including levels of synaptic bombardment that would occur in vivo. Using visualization tools and analyses we assess the ion channel current contribution profile across the different somatic and dendritic compartments of the models. Results: We identify changes in dendritic excitability, ion channel current contributions and co-activation patterns between in vitro and in vivo-like states. Primarily, we find that the relative timing between ion channel currents are mostly invariant between states, but exhibit changes in magnitudes and decreased propagation across dendritic compartments. We also find enhanced dendritic hyperpolarization-activated cyclic nucleotide-gated channel (h-channel) activation during in vivo-like states, which suggests that dendritically located h-channels are functionally important in altering signal propagation in the behaving animal. Conclusions: Overall, we have demonstrated, using computational modelling, the dynamical changes that can occur to ion channel mechanisms governing neuronal spiking. Simultaneous access to dendritic compartments during simulated in vivo states shows that the magnitudes of some ion channel current contributions are differentially altered during in vivo-like states relative to in vitro.

Deciphering how interneuron specific 3 cells control oriens lacunosum-moleculare cells to contribute to circuit function

“…The models upon which the present work is based have been previously published. Detailed descriptions of these models with equations and parameter values can be accessed from Guet-McCreight and Skinner (33) and Sekulic et al (27). Here we provide a brief description:…”

“…In parallel, in previous work using I-S3 cell models (32), we had developed an approach for performing high-resolution parameter searches to find excitatory and inhibitory synaptic input parameter combinations that could generate in vivo -like states, and thus create virtual networks from a particular cell’s perspective. We took advantage of this approach to do the same for these new OLM cell models where we demonstrated that h-channel dendritic currents are consistently enhanced during in vivo -levels of synaptic bombardment (33). Importantly, I-S3 cell inputs are a major source of inhibitory synaptic inputs to OLM cells (13) .…”

“…Importantly, I-S3 cell inputs are a major source of inhibitory synaptic inputs to OLM cells (13) . Overall, these model developments provide an opportunity to do a detailed in silico exploration of the potential contributions of I-S3 cells in a behaving animal via its control over OLM cells during theta activities, given all of our previous findings on OLM cell dendritic h-channels (27, 31), advancements in generating detailed in vivo virtual network simulations (32, 33), and discovery of the activation patterns of I-S3 cells during animal behaviour (16).…”

“…In this study, we use computational modelling and theoretical analyses to examine how I-S3 cells manifest control over OLM cells so as to decipher how these specialized cell types contribute to function. In the strategy implemented in this work, we use the new OLM cell models (27) with synaptic inputs from I-S3 cells as well as other inputs (33), and perform simulations with these models under in vitro and in vivo -like contexts (see Fig 1 illustration), as motivated by experimental data specific to OLM and I-S3 cells. Our explorations in the in vitro context are based on observations from Tyan et al (15) which showed that I-S3 cells could preferentially control the timing of OLM cell spiking at 5 and 10 Hz (theta frequencies) but not at non-theta frequencies.…”

Integration of Within-Cell Experimental Data With Multi-Compartmental Modeling Predicts H-Channel Densities and Distributions in Hippocampal OLM Cells

“…We have previously shown that using virtual networks, or creating in vivo-like representations with multi-compartment cellular models, as done with our earlier OLM cell models (Sekulić and Skinner, 2017), can lead to insights of circuit function from cellular specifics. Further, we have now used the current OLM cell models to do detailed, dendritic explorations of ion channel dynamics that would not be possible to do experimentally (Guet-McCreight and Skinner, 2020). We have also created in vivo-like states with interneuron-specific interneuron models (Guet-McCreight and Skinner, 2019), and used them to make links between in vitro and in vivo studies (Luo et al, 2020).…”