Sanjna Kumari
*1 and Rishikesh Narayanan
11 Cellular Neurophysiology Laboratory, Molecular Biophysics Unit, Indian Institute of Science, Bengaluru 560012, India
*Email:
[email protected]IntroductionGranule cells (GCs) in the dentate gyrus (DG) receive grid-like spatial inputs and contextual inputs from the entorhinal cortex, both broadly tuned to multiple spatial locations. Despite this, GCs elicit sparse spatial firing that is confined to single place fields, thus playing a central role in selective routing of spatial information to the hippocampal circuit. The mechanisms behind the transformation of broadly tuned afferent inputs into sparse and location-specific outputs remains unclear. In this study, we ask if there are physiologically relevant plasticity mechanisms that can mediate selective routing of spatial information towards place-cell emergence and spatial remapping, especially when inhibitory synapses are absent.MethodsWe employed morphologically and biophysically realistic models of DG GCs (Kumari & Narayanan, 2024), receiving grid-like and contextual spatial inputs from the entorhinal cortex. We employed a stochastic search paradigm in the plasticity space involving fold-changes in excitatory synaptic strengths, persistent sodium (NaP), hyperpolarization-activated cyclic nucleotide-gated (HCN), and inward rectifier potassium (Kir) conductances. We validated plasticity combinations that achieved one of four functional targets relevant to DG spatial tuning: conversion of silent neurons to place cells, uphold existing place field firing, spatial remapping to a new location, and suppression of spurious place fields to obtain a single place field (Fig 1).ResultsWhile excitatory synaptic plasticity alone was insufficient to generate valid spatial tuning, conjunctive synaptic and intrinsic plasticity yielded several valid plasticity combinations for all 4 targets (Valid/Total models for 4 targets: 243/142,000, 325/10,000, 139/5,000, 224/50,000). These valid plasticity combinations manifested pronounced heterogeneity across all fold-changes, unveiling plasticity degeneracy where disparate plasticity combinations yielded similar spatial tuning outcomes. Dimensionality reduction analyses revealed low-dimensional structures in intrinsic measurement and parameter spaces of valid models. In contrast, the plasticity space did not manifest strong constraints on plasticity across different components.DiscussionWhile inhibitory synaptic inputs have been studied as mechanisms for sculpting spatial tuning, we show that selective routing of information and suppression of off-field firing can be achieved through intrinsic plasticity. Among intrinsic components, we predict the axonal initial segment Kir conductance as the strongest determinant of spatial selectivity. We demonstrate that disparate combinations of concomitant plasticity in excitatory synaptic and intrinsic conductances can mediate the emergence, refinement, and remapping of place fields. We show that co-dependent plasticity in different neuronal components can enable robust yet flexible spatial representations despite heterogeneities in neuronal composition and plasticity mechanisms.
FIgure 1. Medial and lateral entorhinal cortex inputs impinge on a DG granule cell. Disparate combinations of synaptic and intrinsic plasticity (NaP, HCN, Kir channels) achieved one of four targets: convert silent cell to place cell, uphold existing place field, remap, or suppress spurious firing. Our results show that robust and flexible spatial tuning is achievable through plasticity degeneracy.
ReferencesKumari, S., & Narayanan, R. (2024). Ion-channel degeneracy and heterogeneities in the emergence of signature physiological characteristics of dentate gyrus granule cells. J Neurophysiol, 132(3), 991-1013. https://doi.org/10.1152/jn.00071.2024
