Development and specification of GABAergic cortical interneurons

Abstract

GABAergic interneurons are inhibitory neurons of the nervous system that play a vital role in neural circuitry and activity. They are so named due to their release of the neurotransmitter gamma-aminobutyric acid (GABA), and occupy different areas of the brain. This review will focus primarily on GABAergic interneurons of the mammalian cerebral cortex from a developmental standpoint. There is a diverse amount of cortical interneuronal subtypes that may be categorized by a number of characteristics; this review will classify them largely by the protein markers they express. The developmental origins of GABAergic interneurons will be discussed, as well as factors that influence the complex migration routes that these interneurons must take in order to ultimately localize in the cerebral cortex where they will integrate with the neural circuitry set in place. This review will also place an emphasis on the transcriptional network of genes that play a role in the specification and maintenance of GABAergic interneuron fate. Gaining an understanding of the different aspects of cortical interneuron development and specification, especially in humans, has many useful clinical applications that may serve to treat various neurological disorders linked to alterations in interneuron populations.

Figure 1

Origin of GABAergic Cortical Interneurons. Anatomy of the embryonic telencephalon at approximately embryonic day 13.5 (E13.5), showing the major origins of GABAergic cortical interneurons. A Sagittal (top) view of the telencephalon. The MGE is labeled in pink and represents Lhx6- Nkx2.1-positive areas. MGE-derived interneurons ultimately express either PV or SST in the cerebral cortex. The CGE is labeled in light blue and represents Lhx6-positive, Nkx2.1-negative areas. CGE-derived interneurons ultimately express 5HT3aR in the cortex. The gray-labeled area represents Dlx1/Mash1-expressing areas. The black dotted line represents the migratory route interneuron precursors take to the cortex. B Coronal view of the telencephalon. Interneuronal progenitors originating in the LGE are labeled in blue; MGE-derived progenitors are labeled in green, and interneurons from the preoptic area are labeled in red. Abbreviations: CR, calretinin; CGE, caudal ganglionic eminence; IN, interneuron; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; OB, olfactory bulb; PV, parvalbumin; POA, preoptic area; SST, somatostatin.

Figure 2

Specification of GABAergic Cortical Interneurons. With regard to the specification of MGE-derived interneuronal progenitors, several transcription factors play a role. Shh signaling activates Nk×2.1, which is the key transcription factor in specifying PV- and SST-positive interneurons from this region. Lh×6 and Lh×8 are transcription factors that lie downstream of Nk×2.1; they also aid in the specification of PV and SST interneurons (see text). Sox6 lies downstream of both Nkx2.1 and Lhx6/8. The Dlx homeobox family of genes play a key role in specification of CGE-derived cortical interneurons, although they also function to maintain the PV-expressing subset of MGE-derived interneurons (Dlx5 in particular). Arx is a homeobox transcription factor whose expression is directly affected by Dlx genes; Arx seems to play a role in the migration of interneurons to the cortex. Gsx1 and Gsx2 are both required for the specification of cortical interneurons that originate in the CGE. Mash1 is a downstream transcription factor whose absence results in reduced cortical interneuron numbers; it is required for proper function of the Notch ligand Delta1, which, in the Notch signaling pathway, serves to repress neuronal differentiation. The Dlx genes lie further downstream and play a crucial role in CGE-derived interneuron specification. The molecular mechanisms behind POA interneuron specification are unclear, although Nk×2.1 is expressed by interneurons derived from this area. Lh×6 is not expressed by these interneurons. Nk×5.1 was shown to affect the specification of NPY and Reelin interneurons.