Late Development of the GABAergic System in the Human Cerebral Cortex and White Matter

Abstract

Despite the key role of γ-aminobutyric acid (GABA) neurons in the modulation of cerebral cortical output, little is known about their development in the human cortex. We analyzed several GABAergic parameters in standardized regions of the cerebral cortex and white matter in a total of 38 human fetuses and infants from 19 gestational weeks to 2.7 postnatal years utilizing immunocytochemistry, Western blotting, tissue autoradiography and computer-based cellular quantitation. At least 20% of GABAergic neurons in the white matter migrated toward the cortex over late gestation. After term, migration declined and ended within 6 postnatal months. In parallel, the GABAergic neuronal density increased in the cortex over late gestation, also with a peak at term. From midgestation to infancy, the pattern of GABAA receptor binding changed from uniformly low across all cortical layers to high levels concentrated in the middle laminae; glutamic acid decarboxylase (GAD65 and GAD67) levels differentially increased. Thus, the second half of gestation is a period of rapid development of the cortical GABAergic system that continues into early infancy. This time period corresponds to the peak window of vulnerability to perinatal hypoxia-ischemia in which GABAergic neurons are potentially developmentally susceptible, including in the preterm infant.

Association of impaired neuronal migration with cognitive deficits in extremely preterm infants

“…In addition, CUX1-positive neurons were abundantly distributed throughout the neocortex, including the IZ and SP, at 23 GWs, but they were predominantly localized in the cortical plate at 37 GWs (29) (Supplemental Figure 2, C-E), supporting the notion that later-born excitatory neurons continue to migrate even after 23 GWs. In the human neocortex, a substantial population of GABAergic neurons is thought to migrate radially from the pallium (46), with the peak migration of the GABAergic neurons occurring around term (40 GWs) (47). Therefore, it is difficult to consider that all the observed CUX1-positive neurons at 23 GWs were GABAergic neurons, since we observed a larger number of CUX1-positive neurons in the SP at 23 GWs than at 37 GWs (Supplemental Figure 2, C-E).…”

Impaired Neurodevelopmental Outcome After Mild Germinal Matrix-Intraventricular Hemorrhage

“…16,17 Interestingly, and relevant to these MRI observations, recent studies of human premature brain show that during the developmental period of 25 to 34 weeks, the germinal matrix contributes to the generation and later migration of GABAergic interneurons to cerebral cortex and to association nuclei of the thalamus, both critical for higher-level cognitive functions. [18][19][20][21][22] Disturbance of these latter events could have deleterious consequences for neurodevelopment.…”

Defects of the exchange of amino acids in the perinatal period

“…Продовжу-ється формування мозку -мієлінізація підкіркової білої речовини та розгалуження дендритів і роз-виток синаптичних зв'язків. Цей період відпові-дає максимальній уразливості до перинатальної гіпоксії-ішемії [5,4].…”