GABA Receptor-Mediated Impairment of Intermediate Progenitor Maturation During Postnatal Hippocampal Neurogenesis of Newborn Rats

The neurotransmitter GABA and its receptors assume essential functions during fetal and postnatal brain development. The last trimester of a human pregnancy and early postnatal life involves a vulnerable period of brain development. In the second half of gestation, there is a developmental shift from depolarizing to hyperpolarizing in the GABAergic system, which might be disturbed by preterm birth. Alterations of the postnatal GABA shift are associated with several neurodevelopmental disorders. In this study, we investigated neurogenesis in the dentate gyrus (DG) in response to daily administration of pharmacological GABA (DMCM) and GABA (CGP 35348) receptor inhibitors to newborn rats. Six-day-old Wistar rats (P6) were daily injected (i.p.) to postnatal day 11 (P11) with DMCM, CGP 35348, or vehicle to determine the effects of both antagonists on postnatal neurogenesis. Due to GABA receptor blockade by CGP 35348, immunohistochemistry revealed a decrease in the number of NeuroD1 positive intermediate progenitor cells and a reduction of proliferative Nestin-positive neuronal stem cells at the DG. The impairment of hippocampal neurogenesis at this stage of differentiation is in line with a significantly decreased RNA expression of the transcription factors , , and . Interestingly, the number of NeuN-positive postmitotic neurons was not affected by GABA receptor blockade, although strictly associated transcription factors for postmitotic neurons, , , and , displayed reduced expression levels, suggesting impairment by GABA receptor antagonization at this stage of neurogenesis. Antagonization of GABA receptors decreased the expression of neurotrophins , , and . In contrast to the GABA receptor blockade, the GABA receptor antagonization revealed no significant changes in cell counts, but an increased transcriptional expression of and . We conclude that GABAergic signaling the metabotropic GABA receptor is crucial for hippocampal neurogenesis at the time of rapid brain growth and of the postnatal GABA shift. Differentiation and proliferation of intermediate progenitor cells are dependent on GABA. These insights become more pertinent in preterm infants whose developing brains are prematurely exposed to spostnatal stress and predisposed to poor neurodevelopmental disorders, possibly as sequelae of early disruption in GABAergic signaling.