Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type

Abstract

We describe convergent evidence from transcriptomics, morphology and physiology for a specialized GABAergic neuron subtype in human cortex. Using unbiased single nucleus RNA sequencing, we identify ten GABAergic interneuron subtypes with combinatorial gene signatures in human cortical layer 1 and characterize a novel group of human interneurons with anatomical features never described in rodents having large, “rosehip”-like axonal boutons and compact arborization. These rosehip cells show an immunohistochemical profile (GAD1/CCK-positive, CNR1/SST/CALB2/PVALB-negative) matching a single transcriptomically-defined cell type whose molecular signature is not seen in mouse cortex. Rosehip cells make homotypic gap junctions, predominantly target apical dendritic shafts of layer 3 pyramidal neurons and inhibit backpropagating pyramidal action potentials in microdomains of the dendritic tuft. These cells are therefore positioned for potent local control of distal dendritic computation in cortical pyramidal neurons.

Conserved cell types with divergent features between human and mouse cortex

“…4E), consistent with previous reports demonstrating SST expression in layer 1 of human MTG 19 and different from mouse Lamp5 and Pax6 interneurons 26,27 , which do not express SST . The Inh L1-4 LAMP5 LCP2 type expressed marker genes of rosehip cells, a type of interneuron with characteristic large axonal boutons that we described in a previous study of layer 1 MTG interneurons 19 . With whole cortex coverage, it is clear that this type is not restricted to layer 1 but rather present across all cortical layers.…”

“…Rather, they expressed SST , consistent with expression of this gene in layer 1 and 2 interneurons as discussed above (Fig. 4A, C, E) 19 . The Inh L1-2 GAD1 MC4R type also lacked expression of VIP (Fig.…”

“…For example, the supragranular layers of cortex, involved in cortico-cortical communication, are differentially expanded in mammalian evolution 18 . Furthermore, certain cell types show highly specialized features in human and non-human primate compared to mouse, such as the interlaminar astrocytes 17 , and the recently described rosehip cell 19 , a type of inhibitory interneuron in cortical layer 1 with distinctive morpho-electrical properties. All of these cellular properties are a function of the genes that are actively used in each cell type, and transcriptomic methods provide a powerful method to understand the molecular underpinnings of cellular phenotypes as well as a means for mechanistic understanding of species-specialized phenotypes.…”

Whole cell patch clamp analysis of non-synaptic and synaptic signaling in rodent and human supragranular neocortex

“…In the past decade, increasing attention has been put on special features of the human neocortex microcircuits comparing them to those of other mammals such as non-human primates, carnivores, and rodents (Boldog et al, 2017;Komlósi et al, 2012;Mohan et al, 2015;Molnár et al, 2008;Oláh et al, 2007;Prince and Wong, 1981;Schwartzkroin and Knowles, 1984;Verhoog et al, 2013;Wang et al, 2015;Yáñez et al, 2005). Species-specific differences evidently exist in various anatomical features of the neocortex including the layering, some long-range connections and some intrinsic electrical and morphological properties of nerve cells (Boldog et al, 2017;Mohan et al, 2015;Wang et al, 2015).…”

“…Species-specific differences evidently exist in various anatomical features of the neocortex including the layering, some long-range connections and some intrinsic electrical and morphological properties of nerve cells (Boldog et al, 2017;Mohan et al, 2015;Wang et al, 2015). Yet,it has been thought that basic cellular elements and local synaptic circuits are fairly stereotyped among mammalian species and largely similar for instance between a rodent and a human.…”