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We present a unique, extensive, and open synaptic physiology analysis platform and dataset. Through its application, we reveal principles that relate cell type to synaptic properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Synaptic properties are heterogeneous in most subclass-to-subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, whereas the strength axis accounts for substantial heterogeneity within the subclass. In the human cortex, excitatory-to-excitatory synaptic dynamics are distinct from those in the mouse cortex and vary with depth across layers 2 and 3.

The neocortex is disproportionately expanded in human compared with mouse 1,2 , both in its total volume relative to subcortical structures and in the proportion occupied by supragranular layers composed of neurons that selectively make connections within the neocortex and with other telencephalic structures. Single-cell transcriptomic analyses of human and mouse neocortex show an increased diversity of glutamatergic neuron types in supragranular layers in human neocortex and pronounced gradients as a function of cortical depth 3 . Here, to probe the functional and anatomical correlates of this transcriptomic diversity, we developed a robust platform combining patch clamp recording, biocytin staining and single-cell RNA-sequencing (Patch-seq) to examine neurosurgically resected human tissues. We demonstrate a strong correspondence between morphological, physiological and transcriptomic phenotypes of five human glutamatergic supragranular neuron types. These were enriched in but not restricted to layers, with one type varying continuously in all phenotypes across layers 2 and 3. The deep portion of layer 3 contained highly distinctive cell types, two of which express a neurofilament protein that labels long-range projection neurons in primates that are selectively depleted in Alzheimer's disease 4,5 . Together, these results demonstrate the explanatory power of transcriptomic cell-type classification, provide a structural underpinning for increased complexity of cortical function in humans, and implicate discrete transcriptomic neuron types as selectively vulnerable in disease., (© 2021. The Author(s).)

Elucidating the cellular architecture of the human cerebral cortex is central to understanding our cognitive abilities and susceptibility to disease. Here we used single-nucleus RNA-sequencing analysis to perform a comprehensive study of cell types in the middle temporal gyrus of human cortex. We identified a highly diverse set of excitatory and inhibitory neuron types that are mostly sparse, with excitatory types being less layer-restricted than expected. Comparison to similar mouse cortex single-cell RNA-sequencing datasets revealed a surprisingly well-conserved cellular architecture that enables matching of homologous types and predictions of properties of human cell types. Despite this general conservation, we also found extensive differences between homologous human and mouse cell types, including marked alterations in proportions, laminar distributions, gene expression and morphology. These species-specific features emphasize the importance of directly studying human brain.

Brief experimentally induced seizures have been shown to increase the expression of mRNA encoding basic fibroblast growth factor (FGF-2) in specific brain regions. However, the extent to which this change in mRNA affects the expression of FGF-2 protein in these brain regions has not been examined. In the present study, we exposed rats to brief non-injurious seizures to determine whether this treatment would lead to an increase in FGF-2 protein expression in selected brain regions. Because initial results indicated that the elevation of FGF-2 protein was not significant following acute seizure exposure, we examined both acute and chronic seizure treatment to determine whether FGF-2 protein expression could be increased under conditions of repeated seizures. Brief limbic seizures were induced by minimal electroconvulsive shock (ECS) given as daily treatments for 1 (acute) or 7 (chronic) days. FGF-2 protein was measured in hippocampus, rhinal cortex, frontal cortex, and olfactory bulb at 20, 48, and 72 h following the last seizure. No significant increases in FGF-2 protein were observed in any region following acute ECS. In the chronic ECS-treated groups, significantly elevated FGF-2-like immunoreactivity was found in the frontal and rhinal cortex as compared with the same regions from both control and acute ECS animals. Increases after chronic ECS were maximal at 20 h, and remained significantly elevated as long as 72 h. These increases were predominantly observed for the 24-kDa and 22/22.5-kDa FGF-2 isoforms. Because chronic ECS, which has been shown to be protective against neuronal cell death, induced significantly more FGF-2 immunoreactivity than did acute ECS, we suggest that FGF-2 expression may be an important substrate for the neuroprotective action of non-injurious seizures. A prolonged induction of the high molecular weight isoforms of FGF-2, as occurs after chronic ECS, may selectively reduce the vulnerability of certain brain regions to a variety of neurodegenerative insults.