Development of cortical GABAergic innervation

Abstract

The mature neocortex contains many different classes of GABAergic inhibitory interneurons, distributed, with some degree of selectivity, through six layers, and through many different regions. Some of the events in the early lives of these neurones that may determine their ultimate destination, their maturation and their selective innervation of targets appropriate for each subtype, are discussed. Both time and place of birth influence the class of interneuron that an early post-mitotic interneuronal precursor will become, driven by the selective expression of different combinations of transcription factors in different regions of their birth places in the ganglionic eminence and ventricular zone. The long distance migration of these precursors along tangential routes in marginal, subventricular, and intermediate zones and their final radial movement, into the developing cortex, is regulated by chemical cues, both attractant and repellent. Once they arrive at their final destination, they must integrate into the developing circuitry. As they mature within the cortex, their axons grow and branch in highly specific patterns that may be partially determined by the genetic blueprint for each interneuronal class and partly by the environment in which they find themselves. Finally, as each interneuron class begins to form synapses with only certain postsynaptic targets, cell-cell recognition, most probably via protein-protein interactions across the synaptic cleft, facilitate the formation of appropriate synapses.

Keywords: GABA; cortex; development; ganglionic eminence; inhibition; interneuron; synapse; synaptogenesis.

Figure 1

Cartoon (lower right) summarizing the origins of cortical interneurons and the tangential migratory paths they follow to the developing neocortex (cortical plate and subplate at this stage of development). At first, early born interneurons follow a more ventral route before migrating along the marginal zone overlying the developing cortex. Once the cortical plate has developed, cells in this pathway also migrate along the intermediate zone. Later born neurones follow a more dorsal route and then migrate along the subventricular zone. See insert (top) for layers. On the left, expression patterns of some of the transcription factors that appear to play a role in differentiation and migration are indicated (see color key). The expression of two important extracellular signals, Semaphorin (3A and 3F) and Neuregulin-1 are also indicated. The birth places of somatostatin-containing (SOM), parvalbumin- containing (PV), calretinin- (CR), and calretinin- plus somatostatin-containing (CR + SOM) interneurons are also indicated. Coronal section through the brain of an embryonic mouse (approximately E14). Figure modified from Hernández-Miranda et al. (2010), Heng et al. (2007), Huang (2009b).