Specialized Subpopulations of Deep-Layer Pyramidal Neurons in the Neocortex: Bridging Cellular Properties to Functional Consequences

Abstract

Neocortical pyramidal neurons with somata in layers 5 and 6 are among the most visually striking and enigmatic neurons in the brain. These deep-layer pyramidal neurons (DLPNs) integrate a plethora of cortical and extracortical synaptic inputs along their impressive dendritic arbors. The pattern of cortical output to both local and long-distance targets is sculpted by the unique physiological properties of specific DLPN subpopulations. Here we revisit two broad DLPN subpopulations: those that send their axons within the telencephalon (intratelencephalic neurons) and those that project to additional target areas outside the telencephalon (extratelencephalic neurons). While neuroscientists across many subdisciplines have characterized the intrinsic and synaptic physiological properties of DLPN subpopulations, our increasing ability to selectively target and manipulate these output neuron subtypes advances our understanding of their distinct functional contributions. This Viewpoints article summarizes our current knowledge about DLPNs and highlights recent work elucidating the functional differences between DLPN subpopulations.

Transcriptomic evidence that von Economo neurons are regionally specialized extratelencephalic-projecting excitatory neurons

“…ET neurons possess distinctive intrinsic membrane properties from neighboring non-ET neurons 45,46 . To test whether VENs also have distinctive electrophysiological properties, we took advantage of a very rare opportunity to perform single neuron patch clamp recordings in human insula ex vivo brain slices from a single human donor.…”

“…VENs have also been reported to express serotonin receptor 2B (HTR2B) and dopamine receptor D3 (DRD3) 29 , and the Schizophreniaassociated protein DISC1 4,25 . Additionally, they express transcription factors FEZF2 and CTIP2 26 which are required for generating subcortical projection neurons in mice 30 , and this has been used as evidence that VENs are subcortically-projecting neurons, referred to here as extratelencephalic-projecting excitatory neurons (ET) (though we acknowledge that ET neurons may not strictly project to subcortical structures and may have telencephalic collaterals 31 ). However, Fezf2 is not specific for ET neurons but is also expressed in near-projecting pyramidal neurons in adult mouse 32 , and expression of many cellular marker genes is not conserved between mouse and human 33,34 .…”

Enhancer viruses and a transgenic platform for combinatorial cell subclass-specific labeling

“…We confirmed labeling of L5 PT cells by electrophysiological characterization of labeled vs unlabeled cells in the cortex (Fig 3c,d, Supp Fig 8). Cells labeled by mscRE4 had characteristics of L5 PT neurons, whereas cells that were label-negative more closely matched L5 IT neurons 16 . This experiment demonstrates the utility of these viral tools for electrophysiology experiments targeted to specific neuronal subclasses for which driver lines are not available.…”

“…For illustrative purposes, we also compared the properties of YFP+ and YFP-neurons to 32 L5 pyramidal neurons located in somatosensory cortex from an uninfected mouse. To classify these neurons as IT-like or PTlike, we used Divisive Analysis of Clustering (diana) from the cluster package in R. I h -related membrane properties are known to differentiate IT and PT neurons across many brain regions 16 . As such, features included in clustering were restricted to the I h-related membrane properties -sag ratio, R N and f R .…”

Differential Striatal Axonal Arborizations of the Intratelencephalic and Pyramidal-Tract Neurons: Analysis of the Data in the MouseLight Database

“…Other than these and a neuron having soma 6 in layer 2/3, 8 out of the 11 neurons having soma in layer 6a and targeting thalamus would be corticothalamic neurons. Layer 6 corticothalamic neurons are distinct from PT neurons, and they together constitute extratelencephalic neurons (Baker et al, 2018). Layer 6 striatum-targeting corticothalamic neurons can thus be regarded as a third type of corticostriatal neurons (i.e., other than IT and PT neurons), but here we did not further analyze them.…”