Intrinsic electrophysiological properties predict variability in morphology and connectivity among striatal Parvalbumin-expressing Pthlh-cells

Abstract

Determining the cellular content of the nervous system in terms of cell types and the rules of their connectivity represents a fundamental challenge to the neurosciences. The recent advent of high-throughput techniques, such as single-cell RNA-sequencing has allowed for greater resolution in the identification of cell types and/or states. Although most of the current neuronal classification schemes comprise discrete clusters, several recent studies have suggested that, perhaps especially, within the striatum, neuronal populations exist in continua, with regards to both their molecular and electrophysiological properties. Whether these continua are stable properties, established during development, or if they reflect acute differences in activity-dependent regulation of critical genes is currently unknown. We set out to determine whether gradient-like molecular differences in the recently described Pthlh-expressing inhibitory interneuron population, which contains the Pvalb-expressing cells, correlate with differences in morphological and connectivity properties. We show that morphology and long-range inputs correlate with a spatially organized molecular and electrophysiological gradient of Pthlh-interneurons, suggesting that the processing of different types of information (by distinct anatomical striatal regions) has different computational requirements.

Interneuron diversity in the human dorsal striatum

“…A PTHLH + population was first described in the mouse striatum 20 , where it was characterized as a group of cells that expressed Pvalb in a gradient manner that correlated with their electrophysiological properties, spatial distribution, morphology, and long-range inputs 23 . In the human striatum this population is characterized by the expression of OPN3 , IL1RAPL2 , and THSD4 , and shows a higher abundance in the CN than in the Pu.…”

“…The Pthlh -expressing interneurons represent a novel class on striatal interneurons that is characterized by a variable Pvalb expression level and a broad continuum of intrinsic electrophysiological properties, which correlates with Pvalb levels 20 . This continuum seems to follow a regional gradient pattern within the mouse dorsal striatum suggesting that the different types of striatal cells receive inputs from different brain cortical areas 23 .…”

Syngap1regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex

“…The majority of PV+ cells are classified as fast-spiking (FS) cells, due to their ability to sustain high-frequency discharges of APs ( Figure 5e, right ). However, clusters of atypical PV+ cells have been previously reported in several brain regions including subiculum (Nassar et al, 2015), striatum (Bengtsson Gonzales et al, 2020), hippocampus (Ekins et al, 2020) and somatosensory cortex (Helm et al, 2013). Atypical PV+ cells share many electrophysiological parameters with FS cells; however, they have a slower half width and possess a lower maximal AP firing frequency (Nassar et al, 2015; Bengtsson Gonzales et al, 2018; Ekins et al, 2020; Helm et al, 2013).…”

Community effort to unravel the complex human neuronal landscape exemplified for the striatum

“…The fourth interneuron subcluster was defined by CDH13, SLIT1, MARCH1, and CNTNAP5 expression, and therefore might be involved in axon guidance 27 . To contextualize if this subclassification of PTHLH+ and TAC3+ interneurons reflects the previous observations of gene expression gradients present in striatal interneurons 23,28 across the two striatal regions and delineate interneuron subtypes in CN and PU, we linked the subsets of both interneuron subtypes to location. Calculating tissue association scores, subsets of PTHLH+ and TAC3+ interneurons associated with either CN or PU were identified.…”