Cell type-specific mechanisms of information transfer in data-driven biophysical models of hippocampal CA3 principal neurons

摘要

The transformation of synaptic input into action potential output is a fundamental single-cell computation resulting from the complex interaction of distinct cellular morphology and the unique expression profile of ion channels that define the cellular phenotype. Experimental studies aimed at uncovering the mechanisms of the transfer function have led to important insights, yet are limited in scope by technical feasibility, making biophysical simulations an attractive complementary approach to push the boundaries in our understanding of cellular computation. Here we take a data-driven approach by utilizing high-resolution morphological reconstructions and patch-clamp electrophysiology data together with a multi-objective optimization algorithm to build two populations of biophysically detailed models of murine hippocampal CA3 pyramidal neurons based on the two principal cell types that comprise this region. We evaluated the performance of these models and find that our approach quantitatively matches the cell type-specific firing phenotypes and recapitulate the intrinsic population-level variability in the data. Moreover, we confirm that the conductance values found by the optimization algorithm are consistent with differentially expressed ion channel genes in single-cell transcriptomic data for the two cell types. We then use these models to investigate the cell type-specific biophysical properties involved in the generation of complex-spiking output driven by synaptic input through an information-theoretic treatment of their respective transfer functions. Our simulations identify a host of cell type-specific biophysical mechanisms that define the morpho-functional phenotype to shape the cellular transfer function and place these findings in the context of a role for bursting in CA3 recurrent network synchronization dynamics. Author summaryThe hippocampus is comprised of numerous types of neurons, which constitute the cellular substrate for its rich repertoire of network dynamics. Among these are sharp waves, sequential activations of ensembles of neurons that have been shown to be crucially involved in learning and memory. In the CA3 area of the hippocampus, two types of excitatory cells, thorny and a-thorny neurons, are preferentially active during distinct phases of a sharp wave, suggesting a differential role for these cell types in phenomena such as memory consolidation. Using a strictly data-driven approach, we built biophysically realistic models of both thorny and a-thorny cells and used them to investigate the integrative differences between these two cell types. We found that both neuron classes have the capability of integrating incoming synaptic inputs in a supralinear fashion, although only a-thorny cells respond with bursts of action potentials to spatially and temporally clustered synaptic inputs. Additionally, by using a computational approach based on information theory, we show that, owing to this propensity for bursting, a-thorny cells can encode more information in their spiking output than their thorny counterpart. These results shed new light on the computational capabilities of two types of excitatory neurons and suggest that thorny and a-thorny cells may play distinct roles in the generation of hippocampal network synchronization.