Abstract
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 in vivo study, we investigated neurogenesis in the dentate gyrus (DG) in response to daily administration of pharmacological GABAA (DMCM) and GABAB (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 GABAB 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 Pax6, Ascl1, and NeuroD1. Interestingly, the number of NeuN-positive postmitotic neurons was not affected by GABAB receptor blockade, although strictly associated transcription factors for postmitotic neurons, Tbr1, Prox1, and NeuroD2, displayed reduced expression levels, suggesting impairment by GABAB receptor antagonization at this stage of neurogenesis. Antagonization of GABAB receptors decreased the expression of neurotrophins (BDNF, NT-3, and NGF). In contrast to the GABAB receptor blockade, the GABAA receptor antagonization revealed no significant changes in cell counts, but an increased transcriptional expression of Tbr1 and Tbr2. We conclude that GABAergic signaling via the metabotropic GABAB 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.
Highlights
Very preterm-born children may suffer from significant deficits in executive function, processing speed, and intelligence (Brydges et al, 2018)
The GABAB receptor antagonist CGP administered in a dose of 2 mg/kg led to a decreased number of Nestin+ cells at the dentate gyrus (DG)
The blockade of GABA receptors did not interfere with the expression of hairy-enhancer-of-split 5 (Hes5) and SRY-box transcription factor 2 (Sox2)
Summary
Very preterm-born children may suffer from significant deficits in executive function, processing speed, and intelligence (Brydges et al, 2018). The risk for neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and anxiety are increased two to four times in preterm children, as compared to term-born controls (Rogers et al, 2018). Postnatal rat pups may serve as a model for the human stage of brain development, corresponding to the last trimester of pregnancy. Both in humans and rodents, the hippocampus undergoes developmental changes close to birth (Semple et al, 2013). Supplemented new neurons form highly complex neural circuits, supporting a role for hippocampal neurogenesis in memory, learning, and behavior (Deng et al, 2010; Anacker and Hen, 2017)
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