Integrating EM and Patch-seq data: Synaptic connectivity and target specificity of predicted Sst transcriptomic types

Neural circuit function is shaped both by the cell types that comprise the circuit and the connections between those cell types ¹ . Neural cell types have previously been defined by morphology ^{2, 3} , electrophysiology ^{4, 5} , transcriptomic expression ^6-8 , connectivity ^9-13 , or even a combination of such modalities ^14-16 . More recently, the Patch-seq technique has enabled the characterization of morphology (M), electrophysiology (E), and transcriptomic (T) properties from individual cells ^17-20 . Using this technique, these properties were integrated to define 28, inhibitory multimodal, MET-types in mouse primary visual cortex ²¹ . It is unknown how these MET-types connect within the broader cortical circuitry however. Here we show that we can predict the MET-type identity of inhibitory cells within a large-scale electron microscopy (EM) dataset and these MET-types have distinct ultrastructural features and synapse connectivity patterns. We found that EM Martinotti cells, a well defined morphological cell type ^{22, 23} known to be Somatostatin positive (Sst+) ^{24, 25} , were successfully predicted to belong to Sst+ MET-types. Each identified MET-type had distinct axon myelination patterns and synapsed onto specific excitatory targets. Our results demonstrate that morphological features can be used to link cell type identities across imaging modalities, which enables further comparison of connectivity in relation to transcriptomic or electrophysiological properties. Furthermore, our results show that MET-types have distinct connectivity patterns, supporting the use of MET-types and connectivity to meaningfully define cell types.