An enhanced role and expanded developmental origins for gamma-aminobutyric acidergic interneurons in the human cerebral cortex

Abstract

Human beings have considerably expanded cognitive abilities compared with all other species and they also have a relatively larger cerebral cortex compared with their body size. But is a bigger brain the only reason for higher cognition or have other features evolved in parallel? Humans have more and different types of GABAergic interneurons, found in different places, than our model species. Studies are beginning to show differences in function. Is this expanded repertoire of functional types matched by an evolution of their developmental origins? Recent studies support the idea that generation of interneurons in the ventral telencephalon may be more complicated in primates, which have evolved a large and complex outer subventricular zone in the ganglionic eminences. In addition, proportionally more interneurons appear to be produced in the caudal ganglionic eminence, the majority of which populate the superficial layers of the cortex. Whether or not the cortical proliferative zones are a source of interneurogenesis, and to what extent and of what significance, is a contentious issue. As there is growing evidence that conditions such as autism, schizophrenia and congenital epilepsy may have developmental origins in the failure of interneuron production and migration, it is important we understand fully the similarities and differences between human development and our animal models.

Keywords: evolution; ganglionic eminences; inhibitory interneurons; telencephalon.

Figure 1

The morphology and axonal connections of the major types of GABAergic interneuron are illustrated on the left, with extra information provided in table form on the right. This is a simplified version of all the possible phenotypic sub-types that have been described. Size of text indicates proportion of interneurons expressing a particular molecular marker. Multiple expression of markers is common. There is variation between species (see text). CALB1 and CALB2 are also known as calbindin and calretinin, 5HT3aR is a subtype of ionotropic serotonin receptor, NPY is neuropeptide Y, nNOS is neuronal nitric oxide synthase. Diagram adapted with permission from Zaitsev (2013) with additional information from Wang et al. (2004), Markram et al. (2004), Tricoire et al. (2010), Rudy et al. (2011), Taniguchi et al. (2013) and Zaitsev (2013).

Figure 2

Expression of 13 genes in 18 neocortical regions, and the three divisions of the ganglionic eminences was obtained from RNA seq data, accessed via the database at http://brainspan.org/rnaseq/search/index.html from human fetal tissue aged 8 or 9 post-conceptional weeks; see Table S1 for more details. This figure is a summary of expression patterns observed. For the genes analysed, broadly speaking, expression patterns in the cortex fell into three categories represented by three coloured rectangles; higher expression anteriorly, laterally and ventrally (blue) or higher expression posteriorly and laterally (green) or higher expression anteriorly and medially compared to laterally (turquoise). Four patterns of expression were observed in the ganglionic eminences; equal expression across the ganglionic eminences (orange) higher expression in the MGE (dark red) or higher expression in the CGE (dark yellow). The resulting Venn diagram divides the expression of 13 genes (in italics) between five points of overlap. We propose that a component of the higher expression of some GABAergic genes in the anterior/lateral/ventral cortex derives from a subset of GABAergic precursors generated in the pallium specified by antero-ventral signalling, whereas higher expression of some cortical GABAergic genes in lateral and posterior regions likely derives entirely from inwardly migrating cells (see text for more details). The expression pattern of NGN2 and SP8 is quite different from the rest reflecting their primary roles in determination of glutamatergic identity (NGN2, Wilkinson et al. 2013) and anterior/medial identity (SP8, O’Leary & Sahara, 2008) in the pallium at this stage of development.

Figure 3

Primary cultures of early human fetal cortical cells, prepared according to Ip et al. (2010) after 3 days in vitro are a mixture of cells expressing a variety of markers including TBR1; post-mitotic glutamatergic cortical neurons (A) PAX6; mitotic radial glia-like cells (B) DLX2 and GAD2; markers for intermediate progenitors and neurons committed to the GABAergic lineage (C,D). Protein expression was revealed by immunoperoxidase cytochemistry. Micrographs were kindly provided by Dr Nahidh Al-Jaberi.