Diversity of Interneurons in the Striatum

Striatal interneurons play a crucial role in regulating basal ganglia output, yet their diversity remains less characterized than that of principal neurons. Muñoz-Manchado et al. performed single-cell RNA sequencing (scRNA-seq) on interneurons from the mouse dorsolateral striatum to resolve their molecular and functional complexity. By integrating transcriptomic data with PatchSeq electrophysiological recordings, the researchers identified seven distinct interneuron classes, six of which are GABAergic and one of which is cholinergic.

The study challenges the traditional view of striatal Pvalb-expressing (fast-spiking) interneurons as a distinct class. Instead, molecular analysis revealed that these cells are a subset of a larger population characterized by the expression of the gene Pthlh. Within this Pthlh-expressing group, Pvalb expression exists on a spatial, dorsoventral, and mediolateral gradient rather than being an all-or-none marker. Electrophysiological data confirms that these cells exist in a functional continuum, where intrinsic firing properties correlate with the level of Pvalb expression and the underlying transcriptional latent factors.

Furthermore, the researchers compared striatal interneurons to their cortical and hippocampal counterparts. While some populations, such as Npy/Mia-expressing cells, share high transcriptional similarity across these regions, striatal Pvalb/Pthlh cells are molecularly and electrophysiologically distinct from cortical Pvalb-expressing interneurons. The authors identified specific ion channel expression differences—such as higher levels of Kcna2 and Kcnab1 in striatal cells—that explain the unique intrinsic properties observed in the striatum compared to the cortex.

This paper significantly clarifies the cellular taxonomy of the striatum. By demonstrating that Pvalb is not a marker for a discrete cell type but rather a variable feature of a broader Pthlh-expressing population, this study highlights the risks of using Pvalb-cre mouse lines to target the entire relevant population in functional studies. It provides a more nuanced foundation for future research investigating how striatal circuit activity shapes reinforcement learning and motor control.