Origin and Molecular Specification of Striatal Interneurons

TLDR

The striatum, a major basal ganglia component, contains projection neurons and interneurons, yet the developmental origin of the interneurons remains poorly understood. The authors hypothesize that within the medial ganglionic eminence, radially migrating cells become projection neurons while tangentially migrating cells predominantly form striatal and cortical interneurons. Using focal retrovirus injections into the ventral telencephalon in vitro, they traced that most striatal interneurons tangentially migrate from the MGE or adjacent POa/AEP and express the NKX2.1 homeodomain protein. NKX2.1 is essential for specifying nearly all striatal interneurons, with its expression maintained in cholinergic, calretinin+, and parvalbumin+ cells but downregulated in SOM, NPY, and NOS cells; loss of Nkx2.1, Mash1, or Dlx1/2 disrupts interneuron differentiation—Mash1 affecting early-born and Dlx1/2 affecting late-born populations—while Lhx6 and Lhx7 contribute to subtype specification.

Abstract

The striatum, the largest component of the basal ganglia, contains projection neurons and interneurons. Whereas there is considerable agreement that the lateral ganglionic eminence (LGE) is the origin of striatal projection neurons, less is known about the origin of striatal interneurons. Using focal injections of retrovirus into the ventral telencephalon <i>in vitro</i>, we demonstrate that most striatal interneurons tangentially migrate from the medial ganglionic eminence (MGE) or the adjacent preoptic/anterior entopeduncular areas (POa/AEP) and express the NKX2.1 homeodomain protein. Although the majority of striatal interneurons (cholinergic, calretinin⁺, and parvalbumin⁺) maintain the expression of NKX2.1 into adulthood, most of the interneurons expressing somatostatin (SOM), neuropeptide Y (NPY), and neural nitric oxide synthase (NOS) appear to downregulate the expression of NKX2.1 as they exit the neuroepithelium. Analysis of striatal development in mice lacking <i>Nkx2.1</i> suggests that this gene is required for the specification of nearly all striatal interneurons. Similar analysis of mice lacking the <i>Mash1</i>basic helix–loop–helix (bHLH) or both the <i>Dlx1</i> and<i>Dlx2</i> homeodomain transcription factors demonstrates that these genes are required for the differentiation of striatal interneurons. <i>Mash1</i> mutants primarily have a reduction in early-born striatal interneurons, whereas <i>Dlx1/2</i>mutants primarily have reduced numbers of late-born striatal interneurons. We also present evidence implicating the<i>Lhx6</i> and <i>Lhx7</i> LIM-homeobox genes in the development of distinct interneuron subtypes. Finally, we hypothesize that, within the MGE, radially migrating cells generally become projection neurons, whereas tangentially migrating cells mainly form interneurons of the striatum and cerebral cortex.