Molecules and mechanisms involved in the generation and migration of cortical interneurons

Abstract

The GABA (γ-aminobutyric acid)-containing interneurons of the neocortex are largely derived from the ganglionic eminences in the subpallium. Numerous studies have previously defined the migratory paths travelled by these neurons from their origins to their destinations in the cortex. We review here results of studies that have identified many of the genes expressed in the subpallium that are involved in the specification of the subtypes of cortical interneurons, and the numerous transcription factors, motogenic factors and guidance molecules that are involved in their migration.

Keywords: 5-HT, 5-hydroxytryptamine; AEP, anterior entopeduncular; BDNF, brain-derived neurotrophic factor; CGE, caudal ganglionic eminence; CP, cortical plate; CR, calretinin; CXCR, CXC chemokine receptor; E, embryonic day; GABA, γ-aminobutyric acid; GABAR, GABA receptor; HGF/SF, hepatocyte growth factor/scatter factor; IZ, intermediate zone; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; MZ, marginal zone; NGR, neuregulin; NPY, neuropeptide Y; Nrp, neuropilin; POA, preoptic area; PV, paravalbumin; Robo, Roundabout; SDF-1, stromal-derived factor 1; SHH, sonic hedgehog; SST, somatostatin; SVZ, subventricular zone; VZ, ventricular zone; gene expression; interneuron; migration; neocortex; neuronal specification; subpallium.

Figure 1. Tangential migration of cortical interneuron

(A) Coronal section taken from the brain of an E13.5 GAD67–GFP (green fluorescent protein) transgenic mouse showing the tangential paths of migrating cortical interneurons (arrowheads) generated in the MGE (asterisk). Scale bar: 200 μm. (B) Schematic drawing of (A) illustrating chemorepulsive (red) and chemoattractive (green) gradients established from ventro-dorsal and dorso-ventral parts of the forebrain respectively. (C) Drawing of a coronal section of E15 mouse brain showing the tangential paths of early- (blue broken lines), and late (red broken lines)-born interneurons. Upon the emergence of the CP, an additional migratory path is formed within the subplate (green broken lines). (D) Schema showing the tangential and radial movements of interneurons within the cortical wall at E13.5 and E14.5. Abbreviations: hem, cortical hem; LV, lateral ventricle; PP, preplate; NCx, neocortex; SP, subplate; Sp, septum; St, striatum.

Figure 2. Gene expression patterns in the subpallium

Drawings of medial (A), caudal-intermediate (B) and caudal (C) coronal sections of E13.5 mouse brain showing the expression of different genes in the subpallial domain which give rise to distinct interneuron subpopulations. Broken lines delineate the VZ. Sub-domains that express two or more genes are marked with stripes. (A and B) Pax6 is expressed at high levels in the pallial proliferative zone and thalamic territory, and at a lower level in the subpallial proliferative zone of the LGE. Nkx2.1 is specifically expressed in the VZ and mantle layer of the MGE. It is also expressed in the proliferative zone of the AEP/POA. Nkx6.2 expression is confined to the LGE/MGE border and overlaps with the expression of Pax6/Dlx2 in the LGE, and Nkx2.1/Dlx2 in the MGE. CR+ (CR-positive) and SST+ (SST-positive) interneuron precursors arise specifically from this Nkx6.2/Nkx2.1-expressing territory. Lhx6 expression is confined to the subventricular zone and the mantle layer of the MGE, and it specifies PV+ (PV-positive) interneurons. Its expression does not overlap with Nkx6.2 expression. AEP/POA, thought to give rise to NPY+ (NPY-positive) interneurons, expresses Nkx2.1, Dlx2 and Nkx5.1, as well as Nkx6.2 in its ventral domain. (C) The CGE is anatomically positioned at the most caudal part of the telencephalon where the LGE and MGE fuse. It remains a matter of debate which genes are specifically expressed in this territory. However, abundant evidence indicates that the CGE generates CR+ interneurons. Shown here is the expression of Dlx2, which characterizes all subpallial domains, Pax6 confined to the proliferative zone, and Lhx6. (D) A summary of the expression of different genes in the LGE, MGE, CGE and POA. ++, High level of expression: +, lower level of expression; -, lack of expression. Abbreviations: Gp, globus pallidus; H, hippocampus; NCx, neocortex; St, striatum; Th, thalamus.