Determining how intrinsic cellular properties govern and modulate neuronal input-output processing is a critical endeavour 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 this 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 determine the functional role of IS3 cells in hippocampal microcircuits.
Significance Statement: For any given neuron, its intrinsic properties determine the conversion of synaptic inputs into spike output. Nonetheless, the intrinsic profile of many neuronal types remains largely unknown due to the absence of cell-specific tools and technical challenges. To overcome this, we developed multi-compartment models to make predictions about cellular intrinsic properties and input-output relationships. We used a semi-automated strategy involving populations of models to capture electrophysiological features of the cell type. We focused on type 3 interneuron-specific cells, a class of GABAergic interneurons that may exert disinhibitory control on hippocampal microcircuits. Our models predicted the presence of fast delayed rectifier potassium currents and the absence of slow delayed rectifier channels and this was confirmed experimentally.
Authors report no conflict of interest.
This work was supported by the Canadian Institutes of Health Research Grants to LT and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grants to LT and FKS. OC was supported by the NSERC PhD fellowship. AGM was supported by a NSERC CGS-M, the Mary H. Beatty Fellowship, the Unilever/Lipton OSOTF Graduate Fellowship, and the QEII-GSST Fellowship