The functional organization of excitatory synaptic input to place cells

Abstract

Hippocampal place cells contribute to mammalian spatial navigation and memory formation. Numerous models have been proposed to explain the location-specific firing of this cognitive representation, but the pattern of excitatory synaptic input leading to place firing is unknown, leaving no synaptic-scale explanation of place coding. Here we used resonant scanning two-photon microscopy to establish the pattern of synaptic glutamate input received by CA1 place cells in behaving mice. During traversals of the somatic place field, we found increased excitatory dendritic input, mainly arising from inputs with spatial tuning overlapping the somatic field, and functional clustering of this input along the dendrites over ~10 µm. These results implicate increases in total excitatory input and co-activation of anatomically clustered synaptic input in place firing. Since they largely inherit their fields from upstream synaptic partners with similar fields, many CA1 place cells appear to be part of multi-brain-region cell assemblies forming representations of specific locations.

Glutamate indicators with improved activation kinetics and localization for imaging synaptic transmission

“…Glutamate imaging is a promising approach for studying spatiotemporal patterns of synaptic activity in the intact brain (10,18,20,33) but the relationship between in vivo iGluSnFR signals and synaptic activity, such as presynaptic APs, has not been characterized. To characterize this relationship, we first imaged individual boutons on axons of individual sparsely-labeled glutamatergic neurons during simultaneous cell-attached electrophysiological recordings from the parent cell bodies.…”

“…However, the ability of commonly-used iGluSnFR variants to distinguish synaptic from extra-synaptic signals has not been established. Experiments have measured or bounded the spatial extent of iGluSnFR and SF-iGluSnFR signals under multiple conditions (10,13,(18)(19)(20)(21), but these bounds have been larger than the mean inter-synaptic distance. For example, SF-Venus-iGluSnFR.A184S exhibited signal correlations spanning 3.6 micrometers in visual cortex in vivo (18), corresponding to a volume containing roughly 30 glutamatergic synapses (1,2).…”

“…Methods are needed to distinguish synaptic from extrasynaptic glutamate signals, and to monitor glutamate with the same high spatial specificity achieved by synaptic glutamate receptors. For example, the ability to specifically detect inputs from a neurons’ synaptic partners is needed to understand the nature of dendritic integration, including the spatial arrangement of synaptic inputs (6, 7), mechanisms that govern synaptic plasticity(8, 9), and the transformations that neurons perform on their inputs (10, 11). Linear and rapid measurements are needed to monitor the amount and timing of glutamate release, and high signal-to-noise ratios are needed to monitor release under challenging conditions, such as in deep structures in vivo over single behavioral trials.…”

Emergence of synaptic organization and computation in dendrites

“…While synaptic clustering appears to be near-ubiquitous across brain areas and species ( ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ), there is striking variability in the qualitative characteristics of clusters. The receptive field of a synapse – the sensory feature encoded by the synaptic input – can be used to describe the properties of clusters.…”

Information Theoretic Approaches to Deciphering the Neural Code with Functional Fluorescence Imaging

“…For example, using fluorescent calcium indicators, the functional properties of large populations of neurons can be simultaneously recorded in rodents ( Dombeck et al, 2007 ; Ziv et al, 2013 ; Stirman et al, 2016 ; Sheffield et al, 2017 ; Radvansky and Dombeck, 2018 ; Stringer et al, 2019 ), zebrafish ( Ahrens et al, 2013 ), or invertebrates such as Caenorhabditis elegans ( Nguyen et al, 2016 ) and Drosophila ( Keller and Ahrens, 2015 ; Mann et al, 2017 ). Furthermore, in vivo imaging can assure the genetic identity of the recorded neurons ( Khoshkhoo et al, 2017 ; Sheffield et al, 2017 ; Jing et al, 2018a , b , c ) and can access subcellular structures, allowing for functional recordings from synapses and dendrites using different functional fluorescent indicators ( Sheffield and Dombeck, 2015 ; Scholl et al, 2017 ; Sheffield et al, 2017 ; Jing et al, 2018d ; Marvin et al, 2018 , 2019 ; Adoff et al, 2021 ).…”