Using a Semi-Automated Strategy to Develop Multi-Compartment Models That Predict Biophysical Properties of Interneuron-Specific 3 (IS3) Cells in Hippocampus

Abstract

Determining how intrinsic cellular properties govern and modulate neuronal input–output processing is a critical endeavor for understanding microcircuit functions in the brain. However, lack of cellular specifics and nonlinear interactions prevent experiments alone from achieving this. Building and using cellular models is essential in these efforts. We focus on uncovering the intrinsic properties of mus musculus hippocampal type 3 interneuron-specific (IS3) cells, a cell type that makes GABAergic synapses onto specific interneuron types, but not pyramidal cells. While IS3 cell morphology and synaptic output have been examined, their voltage-gated ion channel profile and distribution remain unknown. We combined whole-cell patch-clamp recordings and two-photon dendritic calcium imaging to examine IS3 cell membrane and dendritic properties. Using these data as a target reference, we developed a semi-automated strategy to obtain multi-compartment models for a cell type with unknown intrinsic properties. Our approach is based on generating populations of models to capture determined features of the experimental data, each of which possesses unique combinations of channel types and conductance values. From these populations, we chose models that most closely resembled the experimental data. We used these models to examine the impact of specific ion channel combinations on spike generation. Our models predict that fast delayed rectifier currents should be present in soma and proximal dendrites, and this is confirmed using immunohistochemistry. Further, without A-type potassium currents in the dendrites, spike generation is facilitated at more distal synaptic input locations. Our models will help to determine the functional role of IS3 cells in hippocampal microcircuits.

Synaptic mechanisms underlying the network state-dependent recruitment of VIP-expressing interneuron-specific interneurons in the CA1 hippocampus

“…Accordingly, based on the dendritic length required to evoke a single AP in different dendritic microdomains (proximal: ˜6 .5 m vs distal: ˜5 .0 m), the minimal number of synapses leading to the AP generation in IS3 cells may correspond to ˜5 on proximal and ˜4 synapses on distal dendrites. This observation indicates that additional mechanisms, such as increased NMDA/AMPA receptor ratio [50], synaptic scaling of AMPARs [63] or dendrite sitespecific distribution of potassium channels [38] may facilitate distal dendritic integration and spike initiation in IS3 cells.…”

“…To predict the input-specific synaptic recruitment of IS3 cells, we took advantage of the previously developed IS3 cell multi-compartment models [38]. Using experimental data for SC-and TA-EPSCs, as well as IPSCs, we fit the weights, rise and decay times for excitatory and inhibitory synapses onto each dendritic compartment and extrapolated a linear distance-dependent weight rule to generate realistic EPSCs and IPSCs across the entire dendritic arbor of the IS3 cell model ( Figure S5A).…”

“…Using these realistic synaptic parameters, we simulated the in vivo-like conditions in IS3 cell model bombarded with synaptic inputs [39]. Two IS3 cell models with (SDprox1; Figure 3,4) and without (SDprox2; Figure S7) dendritic A-type potassium channels were tested, since both model variants sufficiently captured the electrophysiology of IS3 cells [38].…”

“…The models used in this study (SDprox1 and SDprox2) were previously custom-built to simulate electrophysiological characteristics of IS3 cells (ModelDB accession #: 223031) [38]. Models were simulated in the NEURON environment and results were plotted using customized Python and Matlab scripts.…”

Alterations in Intrinsic and Synaptic Properties of Hippocampal CA1 VIP Interneurons During Aging

“…For multi-compartment modeling we used previously developed I-S3 cell models ( Guet-McCreight et al, 2016 ), and simulations were done using the NEURON software environment ( Carnevale and Hines, 2006 ). We included two model variants, which either had A-type K + current in the proximal dendrites (SDprox1) or had A-type K + current restricted to the soma (SDprox2).…”