Interplay of environmental signals and progenitor diversity on fate specification of cortical GABAergic neurons

Abstract

Cortical GABAergic interneurons constitute an extremely diverse population of cells organized in a well-defined topology of precisely interconnected cells. They play a crucial role regulating inhibitory-excitatory balance in brain circuits, gating sensory perception, and regulating spike timing to brain oscillations during distinct behaviors. Dysfunctions in the establishment of proper inhibitory circuits have been associated to several brain disorders such as autism, epilepsy, and schizophrenia. In the rodent adult cortex, inhibitory neurons are generated during the second gestational week from distinct progenitor lineages located in restricted domains of the ventral telencephalon. However, only recently, studies have revealed some of the mechanisms generating the heterogeneity of neuronal subtypes and their modes of integration in brain networks. Here we will discuss some the events involved in the production of cortical GABAergic neuron diversity with focus on the interaction between intrinsically driven genetic programs and environmental signals during development.

Keywords: cell identity; cortical development; inhibitory circuit; interneuron; non-autonomous specification.

FIGURE 1

Ventral telencephalic germinative zones of cortical GABAergic neurons in the rodent embryonic brain. The medial ganglionic eminence (dorsal, dMGE; ventral, vMGE), caudal ganglionic eminence (CGE), and the preoptic area (POA) are responsible for generating virtually all cortical interneurons. In each region, neural progenitor classes are defined by a combinatorial action of transcription factors (Left) that restrict cells to neurochemically defined fates (Right). Distinct classes of inhibitory cells display characteristic morphology, laminar distribution and electrophysiological properties. 5HT3R, serotonin receptor type 3; CR, calretinin; NPY, neuropeptide Y; PV, parvalbumin; RLN, reelin; SST, somatostatin; VIP, vasointestinal active peptide. Genes: ASCL1, achaete-scute family bHLH transcription factor 1 (Mash1, mammalian homologue); Dbx-1, developing brain homeobox 1; CoupTF1/2, chicken ovalbumin upstream promoter transcription factor; Dlx (Dlx1/2/5/6), distal-less homeobox; Gli1, Gli family zinc finger 1; Gsh1/2, GS homeobox 2; Lhx6, LIM homeobox 6; Nkx (Nkx2.1, Nkx5.1, Nkx6.2), NK homeobox family.

FIGURE 2

Mechanisms regulating post-mitotic plasticity and late-fate specification of cortical GABAergic interneurons. (A) Local pyramidal cells modulate laminar positioning of inhibitory neurons in the cortex (Pla et al., 2006; Lodato et al., 2011). (B) Electrical activity (GABA-mediated membrane depolarization, Ca²⁺ transients) can regulate late acquisition of molecular identity in MGE- and CGE-derived interneurons (Berghuis et al., 2004; Borodinsky et al., 2004; De Marco García et al., 2011; Close et al., 2012; Denaxa et al., 2012). (C) Soluble secreted factors can alter the balance of interneuron subtypes through shift in neurochemical identity (Xu et al., 2005; Lopez-Bendito et al., 2008; Cambray et al., 2012; Vogt et al., 2014).