Development, Diversity, and Death of MGE-Derived Cortical Interneurons

Abstract

In the mammalian brain, cortical interneurons (INs) are a highly diverse group of cells. A key neurophysiological question concerns how each class of INs contributes to cortical circuit function and whether specific roles can be attributed to a selective cell type. To address this question, researchers are integrating knowledge derived from transcriptomic, histological, electrophysiological, developmental, and functional experiments to extensively characterise the different classes of INs. Our hope is that such knowledge permits the selective targeting of cell types for therapeutic endeavours. This review will focus on two of the main types of INs, namely the parvalbumin (PV⁺) or somatostatin (SOM⁺)-containing cells, and summarise the research to date on these classes.

Keywords: GABA; cortical interneurons; interneuron development; interneuron diversity; parvalbumin; somatostatin.

Figure 1

Overview of the major morphological interneuron types in the neocortex. Top: illustration of major morphological IN classes. Upper middle, left: representative reconstructions of Martinotti, neurogliaform, and basket cell type in the neocortex; middle: correlation of somatodendritic to morphological type; and right: schematic representation of preferred postsynaptic target of basket, Martinotti, neurogliaform, and bipolar cells on pyramidal cells (PYR). Lower middle: Schematic illustration of the electrical signatures of these four morphological IN types. Slow single spike kinetics are only observed in burst-spiking neurons. Bottom: expressed neurochemical markers in these IN subtypes. Abbreviations: AHP, afterhyperpolarisation; CCK, cholecystokinin; ChAT, choline acetyltransferase; L, cortical layer; nNOS, neuronal nitric oxide synthase; NPY, neuropeptide Y; PV, parvalbumin; PYR, pyramidal cell; SOM, somatostatin; VIP, vasoactive intestinal peptide; and 5HT_3AR, 5HT_3A receptor.

Figure 2

Laminar distribution profile of PV⁺, SOM⁺, VIP⁺, and non-VIP INs in the neocortex. (A) Left panel: schematic illustration of the mouse anterior cingulate cortex containing 1 Martinotti cell (green), 1 neurogliaform cell (grey), and 1 basket cell (magenta). Right Panel: confocal images (maximum intensity projections) of coronal sections of the mouse anterior cingulate cortex labelled for SOM⁺ (left, green), VIP⁺ (middle, white), and PV⁺ (left, magenta) neurons. Nuclei were visualised with DAPI (blue) to identify cortical layers (left and right). (B) Diagram showing the relative fraction of PV⁺ (magenta), SOM⁺ (green), VIP⁺ (dark grey), and non-VIP (light grey) INs as function of the cortical layer. PV and SOM expression can be observed in supra (L2/3) and infragranular (L5/6) layers, whereas that of VIP is restricted to supragranular layers.

Figure 3

Embryonic origin and development of cortical interneurons. (A) Confocal image of a E14.5 coronal brain slice stained for GAD65/67 (grey) and DAPI (blue). The germinative regions (LGE, dMGE, MGE, and POA) are illustrated on the left hemisphere. The expression of distinct transcription factors is illustrated on the right hemisphere. The graded expression of Shh and Wnt is depicted in the middle. (B) Top, left panel: schematic representation of the brain with germinative regions illustrated in dark blue; and right panel: diagram showing the generation of SOM⁺, PV⁺, and 5-HT3AR⁺ INs as a function of developmental age. Bottom: schematic of germinative regions in the embryonic brain and their relative contribution to classes of INs. The MGE gives preferentially rise to PV⁺ and SOM⁺ INs, whereas the CGE primarily produces 5-HT_3AR⁺ INs. The POA in turn produces a mixed population of GABAergic INs. MGE and CGE-derived INs typically coexpress a combination of different neurochemical markers, some of which are illustrated.

Figure 4

Overview of connectivity (presynaptic inputs and postsynaptic outputs) of neocortical PV⁺ and SOM⁺ INs. PV⁺ INs are subdivided into basket and chandelier cells, and SOM⁺ INs are subclassified into Martinotti and non-Martinotti cells. Dendritic spines can be found on PV⁺ basket cells and on Martinotti and non-Martinotti cells. Dendrites of chandelier cells are always aspiny. The main input source onto any IN type represents pyramidal neurons but PV⁺ and SOM⁺ INs also receive inhibitory inputs from other INs. Main output targets of any IN type are pyramidal cells followed by other IN types.