Genetics and function of neocortical GABAergic interneurons in neurodevelopmental disorders

Abstract

A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders.

Figure 1

Interneuron diversity. Interneurons are diverse in terms of their histochemical profile, morphology, physiological properties, and connectivity. In this schematic representation, parvalbumin-positive (PV) interneurons (red) include basket cells forming perisomatic contacts on adjacent pyramidal cells (dark blue), as well as chandelier cells that target the pyramidal cell axon initial segment. Somatostatin-positive (SST) interneurons include Martinotti cells that contact pyramidal cell dendrites in layer I. Vasointestinal peptide (VIP) and calretinin (CR) double-positive bitufted interneurons target pyramidal cells and other interneurons. Neurogliaform cells, marked with reelin, are the most abundant interneurons in layer I and provide tonic GABAergic inhibition via volume transmission of GABA.

Figure 2

Genetic cascade governing cortical interneuron generation. Corticolimbic interneurons originate in the medial and caudal ganglionic eminences (MGE and CGE). The homeobox transcription factors Dlx5/6, Dlx1/2 and the proneural gene Mash1 (not shown) are expressed throughout the ganglionic eminences and are required for the generation of all GABAergic interneurons. The MGE generates parvalbumin-positive (PV) basket cells and chandelier cells, as well as somatostatin-positive (SST) cells (including Martinotti cells). These rely on the sequential expression of Nkx2.1, Lhx6, and Sox6 for proper specification and maturation (see text). The genetic cascade governing the specification of CGE-derived interneurons has not been fully elucidated yet, but Nkx6.2 and Gsh2 are expressed in the CGE and might be important players (see text).