Ion‐channel degeneracy and heterogeneities in the emergence of complex spike bursts in CA3 pyramidal neurons
Authors: Roy Rituparna , Narayanan Rishikesh 
Published: October 2022

AbstractComplex spike bursting (CSB) is a characteristic electrophysiological signature exhibited by several neuronal subtypes and has been implicated in neural plasticity, learning, perception, anaesthesia and active sensing. Here, we address how pronounced intrinsic and synaptic heterogeneities affect CSB, with hippocampal CA3 pyramidal neurons (CA3PNs), where CSB emergence and heterogeneities are well characterized, as a substrate. We randomly generated 12,000 unique models and found 236 valid models that satisfied 11 characteristic CA3PN measurements. These morphologically and biophysically realistic valid models accounted for gating kinetics and somatodendritic expression profiles of 10 active ion channels. This heterogeneous population of valid models was endowed with broad distributions of underlying parameters showing weak pairwise correlations. We found two functional subclasses of valid models, intrinsically bursting and regular spiking, with significant differences in the expression of calcium and calcium‐activated potassium conductances. We triggered CSB in all 236 models through different intrinsic or synaptic protocols and observed considerable heterogeneity in CSB propensity and properties spanning models and protocols. Finally, we used virtual knockout analyses and showed that synergistic interactions between intrinsic and synaptic mechanisms regulated CSB emergence and dynamics. Specifically, although there was a dominance of calcium and calcium‐activated potassium channels in the emergence of CSB, individual deletion of none of the several ion channels or N‐methyl‐d‐aspartate receptors resulted in the complete elimination of CSB across all models. Together, our analyses critically implicate ion‐channel degeneracy in the robust emergence of CSB and other characteristic signatures of CA3PNs, despite pronounced heterogeneities in underlying intrinsic and synaptic properties.
imageKey points
An unbiased stochastic search algorithm yielded a heterogeneous population of morphologically and biophysically realistic CA3 pyramidal neuronal models matching several signature electrophysiological characteristics.
Two functional subclasses of valid models were identified with intrinsically bursting (IB) and regular spiking (RS) characteristics, which exhibited differential localization within the parametric space with linear and non‐linear dimension reduction analyses.
Calcium and calcium‐activated potassium channels distinguished IB from RS models, apart from playing dominant roles in the emergence of complex spike bursting (CSB).
The impact of deleting individual ion channels or N‐methyl‐d‐aspartate receptors was variable across different models and differential for each channel/receptor, pointing to ion‐channel degeneracy in the emergence of CSB.
Biological heterogeneities across different neurons of the same subtype, ion‐channel degeneracy and state‐dependent changes (involving activity‐dependent plasticity, pathology, and neuromodulation of intrinsic and synaptic properties) need to be considered carefully in assessing the propensity and dynamics of CSB in different neuronal subtypes.