Inferring monosynaptic connections from paired dendritic spine Ca2+ imaging and large-scale recording of extracellular spiking

Objective: Techniques to identify monosynaptic connections between neurons have been vital for neuroscience research, facilitating important advancements concerning network topology, synaptic plasticity, and synaptic integration, among others. Approach: Here, we introduce a novel approach to identify and monitor monosynaptic connections using high-resolution dendritic spine Ca2+ imaging combined with simultaneous large-scale recording of extracellular electrical activity by means of high-density microelectrode arrays. Main results: We introduce an easily adoptable analysis pipeline that associates the imaged spine with its presynaptic unit and test it on in vitro recordings. The method is further validated and optimized by simulating synaptically-evoked spine Ca2+ transients based on measured spike trains in order to obtain simulated ground-truth connections. Significance: The proposed approach offers unique advantages as (a) it can be used to identify monosynaptic connections with an accurate localization of the synapse within the dendritic tree, (b) it provides precise information of presynaptic spiking, and (c) postsynaptic spine Ca2+ signals and, finally, (d) the non-invasive nature of the proposed method allows for long-term measurements. The analysis toolkit together with the rich data sets that were acquired are made publicly available for further exploration by the research community.

Automated summary

This article introduces a novel approach to identify and monitor monosynaptic connections between neurons. The method combines high-resolution imaging and large-scale recording of electrical activity. The proposed approach offers unique advantages in accurately localizing synapses, providing precise information of presynaptic spiking, measuring postsynaptic spine Ca2+ signals, and allowing for long-term measurements.