Abstract
Hippocampal pyramidal neurons are endowed with signature excitability characteristics, exhibit theta-frequency selectivity — manifesting as impedance resonance and as a band-pass structure in the spike-triggered average (STA) — and coincidence detection tuned for gamma-frequency inputs. Are there specific constraints on molecular-scale (ion channel) properties in the concomitant emergence of cellular-scale encoding (feature detection and selectivity) and excitability characteristics? Here, we employed a biophysically-constrained unbiased stochastic search strategy involving thousands of conductance-based models, spanning 11 active ion channels, to assess the concomitant emergence of 14 different electrophysiological measurements. Despite the strong biophysical and physiological constraints, we found models that were similar in terms of their spectral selectivity, operating mode along the integrator-coincidence detection continuum and intrinsic excitability characteristics. The parametric combinations that resulted in these functionally similar models were non-unique with weak pair-wise correlations. Employing virtual knockout of individual ion channels in these functionally similar models, we found a many-to-many relationship between channels and physiological characteristics to mediate this degeneracy, and predicted a dominant role for HCN and transient potassium channels in regulating hippocampal neuronal STA. Our analyses reveals the expression of degeneracy, that results from synergistic interactions among disparate channel components, in the concomitant emergence of neuronal excitability and encoding characteristics.
Highlights
Hippocampal pyramidal neurons are endowed with signature excitability characteristics, exhibit theta-frequency selectivity — manifesting as impedance resonance and as a band-pass structure in the spike-triggered average (STA) — and coincidence detection tuned for gamma-frequency inputs
We introduced the following ion channels, with kinetics and gating properties derived from hippocampal pyramidal neurons, into this passive structure: fast sodium (NaF), delayed rectifier potassium (KDR), A-type potassium (KA), M-type potassium (KM), hyperpolarization-activated cyclic-nuclotide gated (HCN) nonspecific cation, L-type calcium (CaL), N-type calcium (CaN), R-type calcium (CaR), T-type calcium (CaT), big- (BK) and small-conductance (SK) calcium-activated potassium channels
The base model measurements showed that the effective coincidence detection window (ECDW) was in the gamma frequency range (Fig. 1j), another characteristic feature of the STA associated with CA1 pyramidal neuronal soma[25]
Summary
Hippocampal pyramidal neurons are endowed with signature excitability characteristics, exhibit theta-frequency selectivity — manifesting as impedance resonance and as a band-pass structure in the spike-triggered average (STA) — and coincidence detection tuned for gamma-frequency inputs. The STA provides quantitative assessments of intrinsic excitability, spectral selectivity and neuronal operating mode along the integrator-coincidence detector (I-CD) continuum These quantifications, showing the STA of hippocampal pyramidal neurons to be endowed with theta-frequency (4–10 Hz) selectivity and gamma-range (25–150 Hz) coincidence detection capabilities[23,24,25,26], place tight constraints on channel properties that result in their emergence[20,21,22,23,24,25,26]. We determined the manner in which different ion channels influence various parameters of a neuron’s STA by generating acute virtual knockouts[9,14,40] of individual ion channels, and by assessing the STA of each virtual knockout model (VKM) We demonstrate that both frequency selectivity and coincidence detection measured from neuronal STA are critically reliant on several ion channels, implying that strong interactions among different ion channels drive operational characteristics and excitability homeostasis in hippocampal pyramidal neurons. Our results provide experimentally well-constrained lines of evidence for the expression of degeneracy in the ability of single neurons to be endowed with similar encoding and excitability characteristics, and in determining their operational mode along the I-CD continuum
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