Transient actions of neurotransmitters during neocortical development.

In certain forms of epilepsy, the neuronal connectivity of the neocortex is aberrant. These altered connections are thought to arise from trauma, toxic or metabolic insult, or a deviation from normal developmental processes. To appreciate the pathophysiology of these epilepsies, however, an understanding of the normal connectivity of the developing cortex is essential. Much evidence suggests that this connectivity differs significantly from that of the mature cortex. Here we focus on how developmentally restricted actions of the amino acid neurotransmitters glutamate, y-aminobutyric acid (GABA), and taurine might function in the transient circuitry of the immature rodent neocortex (see Table 1 for summary). Very early in cortical development, cells destined to give rise to neocortical neurons and glia constitute a proliferative neuroepithelium surrounding the cerebral ventricles. In this ventricular zone, neuroblasts are coupled by gap junctions into discrete radial clusters (1). Cells are believed to uncouple from these clusters only during the M phase of the cell cycle (2). On division, daughter cells either recouple to a cluster and continue as cycling neuroblasts, or migrate, as postmitotic neurons, along radial glia to reach their ultimate laminar position in the cortex. Although coupled, cycling neuroblasts are not, by definition, neurons because they cannot generate action potentials, they do express functional receptors for the amino acid neurotransmitters glutamate and GABA. Activation of both GABA, and non-N-methy1-Daspartate (NMDA) glutamate receptors has been shown to depolarize these cortical progenitor cells, thereby activating voltage-gated calcium channels (VDCCs), which they also express (3). Unexpectedly, activation of these receptors was shown to inhibit the synthesis of DNA, as assayed by the incorporation of the thymidine analogue 5’-bromodeoxyuridine (BrdU), in coupled neuroblasts. Although the mechanism by which GABA and glutamate exert these effects remains to be elucidated, this finding suggests that the ultimate number of cortical neurons can be influenced by amino acid transmitters. By extrapolation, sources that might provide the ventricular zone with these transmitters including postmitotic neurons, thalamocortical fibers, and local clusters themselves, could in turn determine cortical neuronal number. On terminal differentiation in the ventricular zone, newly postmitotic neurons migrate radially into the intermediate zone en route to their final destination in the cortical plate, which will eventually form the cortical laminae. While in the intermediate zone, these neurons begin to express functional glycine receptors in addition to the already present GABA, and non-NMDA receptors (4). As predicted from the relatively high intracellular chloride concentration, activation of the glycine receptor results in depolarization of these migrating neurons. In turn, VDCCs are activated, possibly initiating calciumdependent second messenger events. Although glycine itself is not present in significant amounts in the immature cortex, taurine, an essential amino acid that activates the glycine receptor with comparable efficacy, is transiently expressed at levels exceeding those of any other amino acid in the cortex. In the adult cat, dietary taurine deprivation results in visual disorders and ataxia; however, taurine deprivation of a gravid cat results in blind, ataxic, microencephalic kittens (5) . Together these observations suggest that taurine, through the activation of glycine receptors, may influence neuronal migration. During the first postnatal week in the rodent, the majority of cortical neuronal migration is complete. This period, in which cortical synaptogenesis is highest, has been identified as a critical period for the generation of “whisker barrels” or the cortical representation of the vibrissae and for the induction of NMDA-dependent long-term plasticity of glutamatergic thalamocortical input. Cortical neurons throughout this first postnatal week continue to exhibit transiently elevated intracellular chloride, which renders GABA,-receptor activation depolarizing and in some cases excitatory (6). Unlike in the adult cortex, where the majority of spontaneous synaptic activity in slices is glutamatergic, spon-